EMBARGOED FOR EARLY RELEASE: 6:15 A.M. (CT) THURSDAY, OCTOBER 25, 2012

Media Advisory: To contact Asgeir S. Jakola, M.D., email asgeir.s.jakola@ntnu.no. To contact editorial author James M. Markert, M.D., call Bob Shepard at 205-934-8934 or email bshep@uab.edu.

CHICAGO – In a comparison of strategies for treating low-grade gliomas (brain tumors), patients in Norway treated at a hospital that generally favored early surgical resection (removal) had better overall survival than patients treated at a hospital that favored biopsy and watchful waiting, according to a study appearing in JAMA. The study is being release early online to coincide with its presentation at the European Association of Neurosurgical Societies annual meeting.

“Due to diffuse brain infiltration, low-grade gliomas (LGGs) are usually not considered surgically curable. In fact, the effect of surgery on survival remains unclear because current evidence relies on uncontrolled surgical series alone,” according to background information in the article. “Due to lack of better evidence, management of suspected LGGs has remained one of the major controversies in neuro-oncology and treatment strategies often differ considerably between neurosurgical centers.”

Asgeir S. Jakola, M.D., of St. Olavs University Hospital, Trondheim, Norway, and colleagues conducted a study to examine whether early tumor resection, as the preferred strategy, was associated with improved survival among patients with LGG compared with a strategy favoring biopsy and watchful waiting. The study included patients with LGGs at two Norwegian university hospitals with different surgical treatment strategies. In one hospital, diagnostic biopsies followed by a “wait and scan” approach has been favored (biopsy and watchful waiting), whereas early resections have been advocated in the other hospital (early resection). Histopathology specimens from all adult patients diagnosed with LGG from 1998 through 2009 underwent a blinded histopathological review to ensure uniform classification and inclusion. Follow-up ended April 2011. After the central review of histopathology, 153 patients with diffuse LGG (91 percent of screened cohort) were identified and included in the study; 66 (43 percent) from the center favoring biopsy and watchful waiting and 87 (57 percent) from the center favoring early resection.

There were large regional differences in treatment strategies as biopsy and subsequent watchful waiting was the initial strategy in 47 (71 percent) of LGG patients treated at the center favoring biopsy and watchful waiting compared with only 12 (14 percent) treated at the center favoring early resection. Median (midpoint) follow-up was 7.0 years at the center favoring biopsy and watchful waiting and 7.1 years at the center favoring early resection.

At end of follow-up, 34 patients (52 percent) from the center favoring biopsy and watchful waiting had died compared with 28 patients (32 percent) from the center favoring early resection. The researchers found that overall survival was significantly longer for patients treated at the center favoring early resection over biopsy and watchful waiting. “The survival advantage increased with time: While one year survival was 89 percent vs. 89 percent, the expected 3-year survival was 70 percent vs. 80 percent, expected 5-year survival was 60 percent vs. 74 percent, and expected 7-year survival was 44 percent vs. 68 percent. Median survival at the center favoring biopsy was 5.9 years while median survival is not yet reached where initial resection was preferred.”

“In this comparative population-based study in patients with newly diagnosed LGG, a survival benefit was observed for patients treated at a hospital advocating early resection as opposed to diagnostic biopsy and subsequent watchful waiting,” the authors write. “This significantly strengthens the data in support of early resection in newly diagnosed LGG.”

(doi:10.1001/jama. 2012.12807; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: The Role of Early Resection vs. Biopsy in the Management of Low-Grade Gliomas

In an accompanying editorial, James M. Markert, M.D., of the University of Alabama at Birmingham, writes that “although class I evidence for surgical resection of LGG remains lacking, National Comprehensive Cancer Center practice guidelines in oncology support maximal safe resection as a feasible first line of treatment for LGG.”

“The majority of these studies, but not all ones published in the past 2 decades, support this approach as well. The study by Jakola et al adds further evidence for this approach. A follow-up study of their cohorts, allowing for more definitive measurement of survival and more rigorous assessment of complications, neurologic deterioration, and malignant degeneration, would be valuable.”

(doi:10.1001/jama. 2012.14523; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 23, 2012

Molecular Prognostic Assay May Help Identify Patients at High Risk of Death Despite Small, Node-Negative Lung Tumors

“Low-dose computed tomography screening may increase diagnoses of T1a node-negative non-small-cell lung cancers (NSCLC). One-quarter of these patients die within 5 years. Maximizing the benefit of screening requires a reliable method to identify patients with high mortality risk,” writes Johannes R. Kratz, M.D., of the University of California, San Francisco, and colleagues. “A molecular prognostic assay has been clinically validated for nonsquamous NSCLC, but performance of the assay was not studied in small node-negative tumors.”

As reported in a Research Letter, the study included 269 patients with node-negative tumors of less than 2 cm who had undergone resection of nonsquamous NSCLC. The prognostic test measures the expression of 14 genes using quantitative polymerase chain reaction on RNA extracted from specimens, and assigns patients to low-, intermediate-, and high-risk groups based on clinically validated cutoff values for a calculated risk score. Five-year survival was the primary end point.

The average age of patients was 62 years; median (midpoint) follow-up among survivors was 74 months, and 5-year mortality was 28.6 percent. Ninety-two patients (34.2 percent) were identified as high risk by the prognostic assay; survival was significantly different among the high-risk group (52.3 percent), the intermediate-risk group (69.1 percent), and the low-risk group (83.0 percent). “… these data suggest the potential clinical utility of a new prognostic assay in the postoperative management of node-negative T1a disease. The identification of high-risk patients may further maximize the benefit of early detection of T1a node-negative tumors through low-dose computed tomography screening.”

(JAMA. 2012;308[16]:1629-1631. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Choosing Wisely – Low-Value Services, Utilization, and Patient Cost Sharing

Kevin G. Volpp, M.D., Ph.D., of the Philadelphia Veterans Affairs Medical Center, and colleagues examine the recent Choosing Wisely initiative, which aimed at “encouraging physicians, patients and other health care stakeholders to think and talk about medical tests and procedures that may be unnecessary, and in some instances can cause harm.”

“The Choosing Wisely initiative represents an important first step toward the identification of low-value services, more meaningful because it was a step taken jointly by consumer groups and professional specialties. The next step is to move beyond a list of low-value services toward the testing of approaches to reduce their use, ideally through a combination of benefit design, physician payment policies, and social and professional guidance informed by clinical evidence. Given fiscal realities, reducing low-value services is what will allow continued support for the coverage of high-value services.”

(JAMA. 2012;308[16]:1635-1636. Available pre-embargo to the media at http://media.jamanetwork.com)

What’s Needed Is a Health Care System That Learns – Recommendations From an IOM Report

Mark Smith, M.D., M.B.A., of the California HealthCare Foundation, Oakland, Calif., and co-authors were members of an Institute of Medicine (IOM) committee that produced the recent report, “Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. In this Viewpoint, the authors discuss several recommendations from this report for improving the U.S. health care system.

“The stakes are high. Left unchanged, the U.S. health care system will continue to provide world-class services to some, while others will receive substandard care and experience unnecessary harms. Spiraling costs will continue to strain national, state, and local government; corporate; and family budgets. The actions required to reverse this trend will be notable, substantial, highly disruptive—and absolutely necessary. The choice is not whether or when to begin the overdue transformation, but how.”

(JAMA. 2012;308[16]:1637-1638. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 23, 2012

Media Advisory: To contact Ary Serpa Neto, M.D., M.Sc., email aryserpa@terra.com.br. To contact editorial author Niall D. Ferguson, M.D., M.Sc., call Leslie O’Leary at 416-586-4800, ext.8306; or email lo’leary2@mtsinai.on.ca.

CHICAGO –Among patients without acute respiratory distress syndrome, protective mechanical ventilation with use of lower tidal volumes (the volume of air inhaled and exhaled during each breath) was associated with better outcomes including less lung injury, lower mortality, fewer pulmonary infections and a shorter hospital length of stay, according to a meta-analysis of previous studies, reported in the October 24/31 issue of JAMA.

“Mechanical ventilation is a life-saving strategy in patients with acute respiratory failure. However, unequivocal evidence suggests that mechanical ventilation has the potential to aggravate and precipitate lung injury. In acute respiratory distress syndrome (ARDS), and in a milder form of ARDS formerly known as acute lung injury (ALI), mechanical ventilation can cause ventilator-associated lung injury,” according to background information in the article. “Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with ARDS. It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS.”

Ary Serpa Neto, M.D., M.Sc., of ABC Medical School, Santo Andre, Sao Paulo, Brazil and colleagues conducted a meta-analysis to determine whether conventional (higher) or protective (lower) tidal volumes would be associated with lung injury, mortality, and pulmonary infection in patients without lung injury at the onset of mechanical ventilation. After a search of the medical literature, the researchers identified 20 articles (2,822 participants) that met criteria for inclusion in the study.

Analysis of the data indicated a 67 percent decreased risk of lung injury development and 36 percent decrease in the risk of death in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs. nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Analysis also showed, in protective ventilation groups, a lower incidence of pulmonary infection and lower average hospital length of stay (approximately 7 vs. 9 days, respectively).

“In conclusion, our meta-analysis suggests that among patients without lung injury, protective ventilation with use of lower tidal volumes at onset of mechanical ventilation may be associated with better clinical outcomes. We believe that clinical trials are needed to compare higher vs. lower tidal volumes in a heterogeneous group of patients receiving mechanical ventilation for longer periods,” the authors write.

(JAMA. 2012;308[16]:1651-1659. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Low Tidal Volumes for All?

In an accompanying editorial, Niall D. Ferguson, M.D., M.Sc., of Mount Sinai Hospital and the University of Toronto, writes that the “meta-analysis by Serpa Neto and colleagues serves as a convincing summary that the current knowledge base about low trial volume ventilation is inadequate.”

“In addition to confirming or refuting the benefit of setting lower vs. higher tidal volumes in patients without ARDS, additional trials could address the degree of tidal volume limitation required, the patient populations that may benefit most, and whether to actively seek to limit tidal volumes in spontaneously breathing patients or simply avoid setting higher volumes. The role of intraoperative lung-protective ventilation also needs further study. Given the number of ICU patients receiving mechanical ventilation for whom this question applies (i.e., the 95 percent of patients who do not have ARDS at the time of intubation, such trials would have significant clinical importance and would be highly feasible.”

(JAMA. 2012;308[16]:1689-1690. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Dr. Ferguson is supported by a New Investigator Award from the Canadian Institutes of Health Research (Ottawa, Ontario, Canada). The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 23, 2012

Media Advisory: To contact corresponding author John P. A. Ioannidis, M.D., D.Sc., call Krista Conger at 650-725-5371 or email kristac@stanford.edu. To contact editorial author Andrew D. Oxman, M.D., email oxman@online.no.

CHICAGO – In an examination of the characteristics of studies that yield large treatment effects from medical interventions, these studies were more likely to be smaller in size, often with limited evidence, and when additional trials were performed, the effect sizes became typically much smaller, according to a study in the October 24/31 issue of JAMA.

“Most effective interventions in health care confer modest, incremental benefits,” according to background information in the article. “Large effects are important to document reliably because in a relative scale they represent potentially the cases in which interventions can have the most impressive effect on health outcomes and because they are more likely to be adopted rapidly and with less evidence. Consequently, it is important to know whether, when observed, very large effects are reliable and in what sort of experimental outcomes they are commonly observed. … Some large treatment effects may represent entirely spurious observations. It is unknown how often studies with seemingly very large effects are repeated.”

Tiago V. Pereira, Ph.D., of the Health Technology Assessment Unit, German Hospital Oswaldo Cruz, Sao Paulo, Brazil, and colleagues conducted a study to evaluate the frequency and features of very large treatment effects of medical interventions that are first recorded in a clinical trial. For the study, the researchers used data from the Cochrane Database of Systematic Reviews (CDSR) and assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses.

Among 3,545 available reviews, 3,082 contributed usable information on 85,002 forest plots (a graphical display designed to illustrate the relative strength of treatment effects in multiple studies). Overall, 8,239 forest plots (9.7 percent) had a nominally statistically significant very large effect in the first published trial, group A; 5,158 (6.1 percent) had a nominally statistically significant very large effect found only after the first published trial, group B; and 71,605 (84.2 percent) had no trials with significant very large effects, group C. The researchers found that nominally significant very large effects arose mostly from small trials with few events. For the index trials, the median [midpoint] number of events was only 18 in group A and 15 in the group B. The median number of events in the group C index trials was 14.

The authors also observed that 90 percent and 98 percent of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from approximately 12 to 4 for first trials, and from 10 to 2.5 for subsequent trials.

Topics with very large effects were less likely than other topics to address mortality. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns).

“… this empirical evaluation suggests that very large effect estimates are encountered commonly in single trials. Conversely, genuine very large effects with extensive support from substantial evidence appear to be rare in medicine and large benefits for mortality are almost entirely nonexistent. As additional evidence accumulates, caution may still be needed, especially if there is repetitive testing of accumulating trials. Patients, clinicians, investigators, regulators, and the industry should consider this in evaluating very large treatment effects when the evidence is still early and weak,” the researchers write.

(JAMA. 2012;308[16]:1676-1684. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Dr. Pereira was supported in part by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Sao Paulo Research Foundation). All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Improving the Health of Patients and Populations Requires Humility, Uncertainty, and Collaboration

Andrew D. Oxman, M.D., of the Norwegian Knowledge Centre for the Health Services, Oslo, Norway, comments on the findings of this study in an accompanying editorial.

“Clinicians should be humble about the ability to prevent or treat most health problems, although a large range of effective interventions are available, some with large effects, most have modest (albeit important) effects and the effects of many are uncertain. Acknowledging uncertainty is the first, essential step to reducing important uncertainties through well-designed evaluations. Collaboration is essential to reduce those uncertainties by identifying and agreeing to priorities for evaluation and making sure not to continue to waste scarce resources for research on unimportant questions or poorly designed evaluations. Clinicians need to collaborate on needed evaluations and synthesizing and making the results of evaluations readily available to inform decisions about how best to improve the health of individuals and populations.”

(JAMA. 2012;308[16]:1691-1692. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 23, 2012

Media Advisory: To contact Michel M. Joosten, Ph.D., call Kelly Lawman at 617-667-7305 or email klawman@bidmc.harvard.edu.

CHICAGO – Among nearly 45,000 men who were followed up for more than two decades, those with the risk factors of smoking, hypertension, high cholesterol, and type 2 diabetes had an associated greater risk of developing PAD, according to a study in the October 24/31 issue of JAMA.

“Peripheral artery disease (PAD) is a distinct atherosclerotic syndrome marked by stenosis or occlusion [blockage] of the arteries, particularly of the lower extremities. PAD affects 8 to 10 million individuals in the United States, and is associated with reduced functional capacity and increased risk for cardiovascular morbidity and mortality. Despite its widespread prevalence and negative associations with quality of life, morbidity, and mortality, PAD remains underdiagnosed and undertreated,” according to background information in the article. Preventable or treatable risk factors for PAD are generally thought to be similar to other forms of cardiovascular disease, however their respective associations with risk of PAD and the extent to which they are jointly associated with the incidence of PAD are not well established.

Michel M. Joosten, Ph.D., of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and colleagues conducted a study to estimate the individual and cumulative associations of the 4 conventional cardiovascular risk factors of smoking, hypertension, hypercholesterolemia, and type 2 diabetes with the risk of PAD among men. The study included 44,985 men in the United States without a history of cardiovascular disease at the beginning of the study in 1986; participants in the Health Professionals Follow-up Study were followed up for 25 years until January 2011. The presence of risk factors was updated biennially during follow-up.

During a median (midpoint) follow-up of 24.2 years, there were 537 cases of incident PAD. The researchers found that each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other 3 risk factors and confounders. Regardless of duration category, all men with a risk factor had higher risks of developing PAD compared with men without risk factors. Each additional risk factor approximately doubled the risk for PAD. Men who did not have any of the 4 risk factors had a 77 percent lower risk for developing PAD compared with all other men in the group. In 96 percent of PAD cases, at least 1 of the 4 risk factors was present at the time of PAD diagnosis.

Risk of PAD tended to increase with duration of both type 2 diabetes and hypercholesterolemia. Among men with a positive history of hypertension, risk of PAD was higher among men who reported use of 1 antihypertensive drug or 2 or more antihypertensive drugs compared with men with hypertension who did not report current use of antihypertensive drugs. Cumulative intensity of smoking demonstrated a graded relationship with risk.

“In conclusion, in this well-characterized cohort of U.S. men followed up for longer than 2 decades, smoking, hypertension, hypercholesterolemia, and type 2 diabetes each demonstrated strong, graded, and independent associations with risk of clinically significant PAD,” the authors write.

(JAMA. 2012;308[16]:1660-1667. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 8:15 A.M. (CT) WEDNESDAY, OCTOBER 17, 2012

Media Advisory: To contact Sangeeta Mehta, M.D., call Nicole Bodnar at 416-978-5811 or email Nicole.bodnar@utoronto.ca.
CHICAGO – For critically ill patients receiving mechanical ventilation, daily sedation interruption did not reduce the duration of mechanical ventilation or appear to offer any benefit to patients, and may have increased both sedation and analgesic use and nurse workload, according to a study appearing in JAMA. The study is being published early online to coincide with its presentation at the European Society of Intensive Care Medicine Annual Congress.

“Critically ill patients wean more quickly from mechanical ventilation, with lower risk of delirium, when clinicians use specific strategies to reduce excessive sedation, according to background information in the article. “Protocolized sedation and daily sedative interruption are 2 strategies to minimize sedation and reduce the duration of mechanical ventilation and intensive care unit (ICU) stay.”

Sangeeta Mehta, M.D., of Mount Sinai Hospital and the University of Toronto, and colleagues conducted a study to examine whether mechanically ventilated adults managed with both protocolized sedation and daily sedation interruption would receive less sedation and have a shorter duration of mechanical ventilation than patients managed with protocolized sedation alone. The randomized controlled trial, which included 430 critically ill, mechanically ventilated adults, was conducted in 16 tertiary care medical and surgical ICUs in Canada and the United States between January 2008 and July 2011. Patients received continuous opioid or benzodiazepine infusions and random allocation to protocolized sedation (n = 209) (control) or to protocolized sedation plus daily sedation interruption (n = 214). Using validated scales, nurses titrated infusions to achieve light sedation. For patients receiving daily interruption, nurses resumed infusions, if indicated, at half of previous doses. Patients were assessed for delirium and for readiness for unassisted breathing.

The median (midpoint) time to successful extubation (removal from mechanical ventilation) was 7 days in both groups. The researchers found that there were no significant between-group differences in ICU or hospital lengths of stay, hospital mortality, rates of unintentional device removal, delirium, ICU neuroimaging, tracheostomy, or organ dysfunction. Daily sedation interruption was associated with higher average daily doses of midazolam and fentanyl, and more daily boluses of benzodiazepines and opiates.

Overall, average Sedation-Agitation Scale scores per patient were similar in the 2 groups. However, nurse workload was significantly higher in the interruption group.

“In this multicenter randomized trial, we found that among mechanically ventilated patients receiving continuous sedation, the combined use of protocolized sedation and daily sedative interruption did not improve on the clinical outcomes observed with protocolized sedation alone. Patients in the daily interruption group received more opioids and benzodiazepines, and self-assessed nursing workload was higher for patients in the daily interruption group than the control group; however, these findings are of uncertain clinical importance,” the authors write.

(doi:10.1001/jama.2012.13872. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Funding was provided by the Canadian Institutes of Health Research. Dr. Cook is a Canada Research Chair of the Canadian Institutes for Health Research. Dr. Burns holds a Clinician Scientist Phase 2 Award of the Canadian Institutes for Health Research. Dr. Fowler is a Clinician Scientist of the Heart and Stroke Foundation (Ontario). All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: The presentation of this study can be viewed live online at http://www.esicm.org/news-article/lives-2012-hot-topics-session.

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EMBARGOED FOR EARLY RELEASE: 8:15 A.M. (CT) WEDNESDAY, OCTOBER 17, 2012

Media Advisory: To contact corresponding author Greet Van den Berghe, M.D., Ph.D., email greet.vandenberghe@med.kuleuven.be. To contact editorial author Robert C. Tasker, M.B.B.S., M.D., call Keri Stedman at 617-919-3114 or email keri.stedman@childrens.harvard.edu.

CHICAGO – Although there is some concern that hypoglycemia may adversely affect the developing brain, critically ill children who had been treated with tight glucose control during an intensive care unit admission did not have a worse measure of intelligence four years later than children who received usual care, despite frequent, brief episodes of hypoglycemia, according to a study appearing in the October 24/31 issue of JAMA. The study is being published early online to coincide with its presentation at the European Society of Intensive Care Medicine Annual Congress.

In critically ill children, hyperglycemia may deleteriously affect brain integrity and cognition. In 2009, a large randomized controlled trial with 700 patients revealed that tight glucose control (TGC) to normoglycemia reduced intensive care illness and death compared with usual care (UC), but increased hypoglycemia. Symptomatic hypoglycemia in young children has been associated with variable brain damage. “Therefore, the use of TGC in young patients in the intensive care unit (ICU) may have both beneficial and deleterious effects on various parts of the developing brain, with potentially long-term consequences for neurocognitive development,” according to background information in the article.

Dieter Mesotten, M.D., Ph.D., of the Catholic University of Leuven, Belgium, and colleagues conducted a long-term follow-up of a clinical trial that included 700 patients to exclude possible harm evoked by TGC in critically ill children during ICU treatment, and to validate short-term benefits. The randomized controlled trial included patients ages 16 years or younger who were admitted to the pediatric ICU of the University Hospitals in Leuven, Belgium, between October 2004 and December 2007. Follow-up was scheduled after 3 years with infants assessed at 4 years old between August 2008 and January 2012. For comparison, 216 healthy siblings and unrelated children were tested.

The primary outcomes measured for the study were intelligence (full-scale intelligence quotient [IQ]), as assessed with age-adjusted tests. Further neurodevelopmental testing encompassed tests for visual-motor integration; attention, motor coordination, executive functions; memory; and behavior.

Of the 700 patients in the study, 569 patients were alive and eligible for testing at follow-up. Twenty-seven children could not be reached and 86 children declined participation (16 percent of the total population, no difference between TGC and UC groups). At a median (midpoint) of 3.9 years after randomization, TGC in the ICU did not affect full-scale IQ score (median 88.0 vs. 88.5 for UC). The number of patients with a poor outcome (death or disability) at follow-up was similar in the TGC (68/349 [19 percent]) and UC (63/351 [18 percent]) groups. Other scores for intelligence, visual-motor integration, and memory also did not differ between groups. Brief hypoglycemia evoked by TGC was not associated with worse neurocognitive outcome. In the TGC group, motor coordination was actually improved (9 percent to 20 percent better) and also cognitive flexibility (19 percent better).

The authors write that their data “provide evidence that some of the neurocognitive impairment previously reported in children who have been critically ill could be beneficially affected by altering medical care.”

“In conclusion, 4 years after childhood critical illness, TGC to age-adjusted normoglycemia in an experienced ICU, despite having frequently evoked brief episodes of hypoglycemia, did not cause any detectable harm to intelligence and improved other areas of cognition.”

(JAMA. 2012;308[16]:1641-1650. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Please Note: The presentation of this study can be viewed live online at http://www.esicm.org/news-article/lives-2012-hot-topics-session.

Editorial: Pediatric Critical Care, Glycemic Control, and Hypoglycemia – What Is the Real Target?

In an accompanying editorial, Robert C. Tasker, M.B.B.S., M.D., of Boston Children’s Hospital, writes that “future studies should build on these findings to address additional questions, such as is the global neurocognitive deficit a reflection of pre-morbid state and genetic disease?”

“If this is the case, perhaps there is little that can be achieved except for improving the practice of intensive care. Alternatively, is the neurocognitive morbidity a consequence of cumulative and many different noxious agents and insults during anesthesia and postoperative intensive care? If this is the case, physicians and other caregivers now have a new target and an imperative to follow up all critically ill children who receive pediatric ICU care.”

(JAMA. 2012;308[16]:1687-1688. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Tasker reported being a co-investigator of the Control of Hyperglycaemia in Paediatric Intensive Care study.

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EMBARGOED FOR EARLY RELEASE: 11:15 A.M. (CT) THURSDAY, OCTOBER 18, 2012

Media Advisory: To contact Tarak K. Trivedi, B.S., call John Easton at 773-795-5225 or email john.easton@uchospitals.edu.

CHICAGO – In a study that included more than 300 Medicare-certified nursing homes, rates of hospitalization and death were substantially increased during outbreaks of norovirus gastroenteritis vs. non-outbreak periods, according to a study appearing in the October 24/31 issue of JAMA. The study is being published early online to coincide with its presentation at the ID (infectious disease) Week meeting.

“In the United States, nursing homes annually provide care to approximately 3.3 million residents’ and 22 percent of all deaths occur in these settings. Gastroenteritis outbreaks are common in nursing homes in high-income countries. Annually, more than 1,000 outbreaks of acute gastroenteritis are reported by nursing homes to U.S. public health agencies, and this likely represents only a fraction of the actual number due to underreporting. Although nearly half of all reported nursing home gastroenteritis outbreaks are never etiologically [the cause] confirmed because of challenges in performing diagnostic testing, norovirus is implicated in 86 percent of etiologically confirmed outbreaks,” according to background information in the article. Because hospitalizations and deaths are common among the vulnerable, elderly population in nursing homes, it is difficult to ascertain if there is actually a greater number of these events during norovirus outbreaks.

Tarak K. Trivedi, B.S., a 4^th year medical student at the University of Chicago Pritzker School of Medicine, and colleagues conducted a study to assess the association between norovirus outbreaks and excess all-cause hospitalization and mortality in nursing homes. The study included 308 Medicare-certified nursing homes in Oregon, Wisconsin, and Pennsylvania that reported at least 1 confirmed or suspected norovirus outbreak to the Centers for Disease Control and Prevention’s National Outbreak Reporting System (NORS), January 2009 to December 2010. Deaths and hospitalizations occurring among residents of these nursing homes were identified through the Medicare Minimum Data Set (MDS). Rates of all-cause hospitalization and mortality during outbreak periods were compared with rates during non-outbreak periods, after adjusting for seasonality.

The nursing homes in the study reported a total of 407 norovirus outbreaks. The median (midpoint) duration of outbreaks was 13 days. Hospitalizations and deaths were reported in 119 (29 percent) and 30 (7 percent) outbreaks, respectively. A total of 67,730 hospitalizations and 26,055 deaths were reported in the nursing home cohort during follow-up. Nursing homes experienced 2,533 hospitalizations (124.0/home-year) and 1,097 deaths (53.7/ home-year) during outbreak periods compared with 65,197 hospitalizations (109.5/home-year) and 24,958 deaths (41.9/home-year) during non-outbreak periods. After adjusting for seasonality by month, the rates of hospitalization and death were significantly elevated during outbreak periods.

The increase in hospitalizations was concentrated in the initial week and the subsequent week, and the increased mortality rate was concentrated in the initial week, relative to outbreak onset. In subsequent weeks, the rates of hospitalizations and deaths returned to the levels observed in non-outbreak periods.

The researchers found that nursing homes with lower daily RN hours per resident had a significantly increased rate of mortality during norovirus outbreaks compared with baseline, while no increased risk was observed in homes with higher daily RN hours per resident. The increase in hospitalization rates did not show a similar pattern.

“In conclusion, we detected a consistently increased risk of hospitalization and death from all causes during norovirus outbreaks among residents in nursing homes from 3 U.S. states. As a next step, research should be directed to determine if this increase is directly attributable to norovirus infection and subsequent disease resulting from gastroenteritis. Additionally, more detailed information is necessary to understand the specific contributory causes and comorbidities of norovirus-associated deaths. Given the lack of diagnostic testing in sporadic illness, outbreaks may provide the best opportunities for identifying such associations between norovirus disease and deaths,” the authors write.

“At present, strategies for averting these severe outcomes include general treatment for dehydration and infection control to prevent and control outbreaks. More targeted interventions would be welcome and in light of recent progress with a norovirus vaccine, these results highlight a setting and population that may benefit if efficacy and safety of immunization can be demonstrated.”

(doi:10.1001/jama.2012.14023. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR EARLY RELEASE: 9:30 A.M. (CT) WEDNESDAY, OCTOBER 17, 2012

Media Advisory: To contact J. Michael Gaziano, M.D., M.P.H., call Tom Langford at 617-534-1605 or email tlangford@partners.org.

CHICAGO – In a randomized trial that included nearly 15,000 male physicians, long-term daily multivitamin use resulted in a modest but statistically significant reduction in cancer after more than a decade of treatment and follow-up, according to a study appearing in JAMA. The study is being published early online to coincide with its presentation at the Annual American Association for Cancer Research Frontiers in Cancer Prevention Research meeting.

“Multivitamins are the most common dietary supplement, regularly taken by at least one-third of U.S. adults. The traditional role of a daily multivitamin is to prevent nutritional deficiency. The combination of essential vitamins and minerals contained in multivitamins may mirror healthier dietary patterns such as fruit and vegetable intake, which have been modestly and inversely associated with cancer risk in some, but not all, epidemiologic studies. Observational studies of long-term multivitamin use and cancer end points have been inconsistent. To date, large-scale randomized trials testing single or small numbers of higher-dose individual vitamins and minerals for cancer have generally found a lack of effect,” according to background information in the article. “Despite the lack of definitive trial data regarding the benefits of multivitamins in the prevention of chronic disease, including cancer, many men and women take them for precisely this reason.”

J. Michael Gaziano, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, (and also Contributing Editor, JAMA), and colleagues analyzed data from the Physicians’ Health Study (PHS) II, the only large-scale, randomized, double-blind, placebo-controlled trial testing the long-term effects of a common multivitamin in the prevention of chronic disease. The trial includes 14,641 male U.S. physicians, initially age 50 years or older, including 1,312 men with a history of cancer at randomization, who were enrolled in a multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011. Participants received a daily multivitamin or equivalent placebo. The primary measured outcome for the study was total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points.

PHS II participants were followed for an average of 11.2 years. During multivitamin treatment, there were 2,669 confirmed cases of cancer, including 1,373 cases of prostate cancer and 210 cases of colorectal cancer, with some men experiencing multiple events. A total of 2,757 (18.8 percent) men died during follow-up, including 859 (5.9 percent) due to cancer. Analysis of the data indicated that men taking a multivitamin had a modest 8 percent reduction in total cancer incidence. Men taking a multivitamin had a similar reduction in total epithelial cell cancer. Approximately half of all incident cancers were prostate cancer, many of which were early stage. The researchers found no effect of a multivitamin on prostate cancer, whereas a multivitamin significantly reduced the risk of total cancer excluding prostate cancer. There were no statistically significant reductions in individual site-specific cancers, including colorectal, lung, and bladder cancer, or in cancer mortality.

Daily multivitamin use was also associated with was a reduction in total cancer among the 1,312 men with a baseline history of cancer, but this result did not significantly differ from that observed among 13,329 men initially without cancer.

The researchers note that total cancer rates in their trial were likely influenced by the increased surveillance for prostate-specific antigen (PSA) and subsequent diagnoses of prostate cancer during PHS II follow-up starting in the late 1990s. “Approximately half of all confirmed cancers in PHS II were prostate cancer, of which the vast majority were earlier stage, lower grade prostate cancer with high survival rates. The significant reduction in total cancer minus prostate cancer suggests that daily multivitamin use may have a greater benefit on more clinically relevant cancer diagnoses.”

The authors add that although numerous individual vitamins and minerals contained in the PHS II multivitamin study have postulated chemopreventive roles, it is difficult to definitively identify any single mechanism of effect through which individual or multiple components of their tested multivitamin may have reduced cancer risk. “The reduction in total cancer risk in PHS II argues that the broader combination of low-dose vitamins and minerals contained in the PHS II multivitamin, rather than an emphasis on previously tested high-dose vitamins and mineral trials, may be paramount for cancer prevention. … The role of a food-focused cancer prevention strategy such as targeted fruit and vegetable intake remains promising but unproven given the inconsistent epidemiologic evidence and lack of definitive trial data.”

“Although the main reason to take multivitamins is to prevent nutritional deficiency, these data provide support for the potential use of multivitamin supplements in the prevention of cancer in middle-aged and older men,” the researchers conclude.

(doi:10.1001/jama.2012.14641. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health and an investigator-initiated grant from BASF Corporation. Study agents and packaging were provided by BASF Corporation and Pfizer (formerly Wyeth, American Home Products, and Lederle), and study packaging was provided by DSM Nutritional Products, Inc. (formerly Roche Vitamins). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 16, 2012

Study Finds Association Between Pseudoephedrine Sales and Illicit Manufacture of Methamphetamine

“The illicit production of methamphetamine [a highly addictive stimulant drug] from the precursor pseudoephedrine in clandestine laboratories fuels up to 35 percent of the domestic supply. Public health, law enforcement, and medical associations support restricted access to methamphetamine precursors; manufacturers oppose restrictions,” writes Jeffery Talbert, Ph.D., of the University of Kentucky College of Pharmacy, Lexington, and colleagues. Kentucky law limits pseudoephedrine sales in all counties to 7.2 grams/person/month (as of July 2012, formerly 9 grams/person/month), sufficient to allow a patient to take the maximum daily dose (240 mg/d) each day. Electronic tracking of sales is also required. Despite these restrictions, increases in the number of reported methamphetamine laboratory seizures (called laboratories) continue.

As reported in a Research Letter, the authors analyzed the relationship between pseudoephedrine sales and the number of laboratories reported in Kentucky using county level data from 2010. Law enforcement regulations define laboratories as “requiring two or more chemicals or two or more pieces of equipment used in manufacturing methamphetamine.” The authors found that in 2010, Kentuckians purchased an average of 24,664 g of pseudoephedrine per county and 1,072 laboratories were reported. There was considerable variability in pseudoephedrine sales per county. Counties with greater pseudoephedrine sales were significantly associated with having greater numbers of laboratories. “The strength of this study is that it is the first, to our knowledge, to provide empirical evidence that pseudoephedrine sales are correlated with the clandestine manufacture of methamphetamine,” the researchers write. “… this study highlights the need for research on various approaches to containing clandestine methamphetamine production, including restriction of pseudoephedrine sales to only those patients who have a true medical need for its decongestant properties.”

(JAMA. 2012;308[15]:1524-1526. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

The Problem With Peripherally Inserted Central Catheters

Vineet Chopra, M.D., M.Sc., of the University of Michigan, Ann Arbor, and colleagues write that peripherally inserted central catheters (PICCs) are venous catheters that are inserted peripherally and terminate in central veins such that they may be categorized as central venous catheters. In this Viewpoint, the authors examine the potential complications and harms associated with PICCs.

“The use of PICCs increases each year, which has generated many questions but fewer answers. A research agenda dedicated to understanding best practices and broadening the evidence base for these devices is needed. Until these data are available, physicians should exercise restraint when placing PICCs. Indeed, an ounce of prevention appears obligatory when it comes to avoiding PICC-related complications.”

(JAMA. 2012;308[15]:1527-1528. Available pre-embargo to the media at http://media.jamanetwork.com)

Family Matters in Health Care Delivery

“Although conceptually embraced by policy makers and professional societies, the health care system’s orientation toward family is often an afterthought. Barriers to systematic and explicit acknowledgment and support of families include the bioethical emphasis on patient autonomy, legal concerns surrounding patient privacy and confidentiality, and the prevailing health insurance model grounded in individual coverage,” writes Jennifer L. Wolff, Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore. The author “suggests that more explicit acknowledgment and support of family in health care processes could advance the triple aim of better health, higher-quality care, and reduced costs for patients who are vulnerable and whose care is most costly.”

“Attaining patient- and family-centered care requires moving beyond rhetoric to concrete action, such as making health information routinely available to family members according to a patient’s expressed interests, incorporating aspects of family attributes and care in the electronic health record, tracking who other than the patient is involved in contributing ‘patient-reported’ measures, and screening family caregivers at risk of burnout. Because family truly matters in producing and providing care, efforts to advance the patient-family-clinician partnership may bring practical benefit in the realm of health, quality, and costs.”

(JAMA. 2012;308[15]:1529-1530. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 16, 2012

Media Advisory: To contact Sheila Isanaka, Sc.D., call Marge Dwyer at 617-432-8416 or email mhdwyer@hsph.harvard.edu.

CHICAGO – Among patients with human immunodeficiency virus (HIV) infection in Tanzania, high-dose multivitamin supplementation after beginning highly active antiretroviral therapy did not reduce the risk of HIV disease progression or death compared with standard-dose multivitamin supplements, but did result in the adverse effect of increased levels of a certain liver enzyme, according to a study in the October 17 issue of JAMA.

“During the last 15 years, the provision of highly active antiretroviral therapy (HAART) has significantly decreased morbidity and mortality associated with HIV infection,” according to background information in the article. Despite the substantial health benefits resulting from HAART, there are certain limitations to its efficacy. “Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce HIV disease progression and mortality among individuals not receiving HAART; however, the safety and efficacy of such supplementation has not been established in the context of HAART.”

Sheila Isanaka, Sc.D., of the Harvard School of Public Health, Boston, and colleagues conducted a study to test the hypothesis that high-dose multivitamin supplementation compared with standard-dose supplementation decreases the risk of HIV disease progression or death. The study, conducted between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania, consisted of a randomized controlled trial of high-dose vs. standard-dose multivitamin supplementation for 24 months in 3,418 patients with HIV initiating HAART. Patients received daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance.

The study was stopped early in March 2009 because of evidence of increased levels of the liver enzyme alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement At the time of stopping (median [midpoint] follow-up, 15 months), there were a total of 2,374 HIV disease progression events and 453 deaths (n = 2,460 for combined end point of HIV disease progression or death from any cause). HIV disease progression or death occurred in 1,231 of 1,710 patients (72.0 percent) in the high-dose group and in 1,229 of 1,708 patients (72.0 percent) in the standard-dose group. There was also no appreciable difference between groups in the risk of HIV progression or death from any cause, baseline CD4 count, hemoglobin level, or HAART regimen.

“The ALT above the upper level of normal and the ALT 5 times the upper level of normal were reported in 38 percent (n = 1,118) and 2 percent (n = 54) of patients with ALT measurements, respectively. The incidence of ALT above the upper level of normal was significantly greater among patients in the high-dose supplementation group than the standard-dose supplementation group [1,239 events vs. 879 events],” the authors write.

“Although the provision of high-dose vitamin supplements has been safe among patients infected with HIV not receiving HAART, safety cannot be presumed in the context of potent combination therapies due to potential negative interactions among nutrients and antiretroviral drugs,” the researches write. “Further investigation is required to understand how micronutrient supplements can be best positioned alongside antiretroviral drugs to reduce morbidity and mortality due to HIV. As different doses may have different effects, dose-finding trials with a placebo control are warranted to confirm the potential benefits of multivitamin supplementation on clinical outcomes, and to identify the lowest safe and effective dose in the context of HAART.”

“The adverse effect of high-dose multivitamins compared with standard-dose multivitamins to increase ALT level is a reason for concern, but the mechanism by which multivitamins resulted in this adverse effect is not well understood. In the absence of clear evidence of the benefit of high-dose micronutrient supplementation on morbidity and mortality in adults receiving HAART, it is prudent to follow current recommendations to promote and support adequate dietary intake of micronutrients at recommended dietary allowance levels.”

(JAMA. 2012;308[15]:1535-1544. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the National Institute of Child Health and Human Development. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 16, 2012

Media Advisory: To contact corresponding author Rinaldo Bellomo, M.D., F.C.I.C.M., email rinaldo.bellomo@austin.org.au. To contact editorial co-author Sushrut S. Waikar, M.D., M.P.H., call Jessica Maki at 617-534-1603 or email jmaki3@partners.org.

CHICAGO – In a pilot study assessing the effect of different levels of chloride in intravenous fluids administered to critically ill patients in an intensive care unit, restricting the amount of chloride administration was associated with a significant decrease in the incidence of acute kidney injury and the use of renal replacement therapy, according to a study in the October 17 issue of JAMA.

“The administration of intravenous chloride is ubiquitous in critical care medicine,” according to background in the article. Many of the fluids used for hydration and resuscitation contain supraphysiological (an amount greater than normally found in the body) concentrations of chloride, which may have several adverse effects, including renal vasoconstriction and decreased glomerular filtration rate (GFR). “These effects of chloride on the kidney are of potential concern because acute kidney injury (AKI) is associated with high mortality and may require treatment with costly and invasive renal replacement therapy (RRT).”

Nor’azim Mohd Yunos, M.D., of Monash University Sunway Campus, Malaysia, and colleagues conducted a study to examine whether a chloride-restrictive intravenous fluid strategy for critically ill patients might be associated with a decreased incidence and severity of AKI compared with a chloride-liberal intravenous strategy. The study included 760 patients admitted to an intensive care unit (ICU) during the control period (February 18 to August 17, 2008) compared with 773 patients admitted during the intervention period (February 18 to August 17, 2009) at a university-affiliated hospital in Melbourne, Australia. During the control period, patients received standard intravenous fluids. After a 6-month phase-out period (August 18, 2008 to February 17, 2009), any use of chloride-rich intravenous fluids (0.9 percent saline, 4 percent succinylated gelatin solution, or 4 percent albumin solution) was restricted to attending specialist approval only during the intervention period; patients instead received a lactated solution (Hartmann solution), a balanced solution (Plasma-Lyte 148), and chloride-poor 20 percent albumin.

The primary outcomes included increase from baseline to peak creatinine level in the ICU and incidence of AKI according to the risk, injury, failure, loss, end-stage (RIFLE) classification. Secondary analysis outcomes included the need for renal replacement therapy, length of stay in ICU and hospital, and survival.

During the intervention period, chloride administration decreased from 694 to 496 mmol/patient. The chloride-restrictive strategy was associated with a significantly lower increase in serum creatinine level during ICU stay and a decrease in the incidence of injury and failure class of RIFLE-defined AKI. “It was further associated with a decrease in RRT use for 78 patients (10 percent) during the control period vs. 49 patients (6.3 percent) during the intervention period,” the authors write.

After adjusting for various factors, including sex, diagnosis, operative status, baseline serum creatinine level, and admission type (elective or emergency), the overall incidence of injury and failure class of RIFLE-defined AKI and the use of RRT remained significantly lower during the intervention period. In addition, there were no differences in long-term dialysis requirements, in-hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge.

“The findings of this study show that a chloride-restrictive intravenous strategy is associated with a decrease in the incidence of the more severe stages of AKI and the use of RRT. These findings, together with the previously reported observations that a chloride-liberal intravenous strategy can be associated with higher cost, and the easy availability of cheap alternatives suggest the need to exert prudence in the administration of fluids with supraphysiological concentrations of chloride, especially in critically ill patients with evidence of early acute renal dysfunction or at risk of acute dysfunction,” the researchers write. “Our findings need to be confirmed in different health care systems and different ICUs.”

(JAMA. 2012;308[15]:1566-1572. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Story reported receiving an unconditional research grant from Baxter Healthcare to fund other fluid studies. No other authors reported disclosures.

Editorial: Saving the Kidneys by Sparing Intravenous Chloride?

Sushrut S. Waikar, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., of the Stanford University School of Medicine, Palo Alto, Calif., (and also Contributing Editor, JAMA), comment on the findings of this study in an accompanying editorial.

“The findings of Yunos and colleagues are important and should serve to focus more attention on the formulation of intravenous fluids. In light of the central role for intravenous fluids in perioperative, intensive, and nonintensive hospital care and the effects of fluid administration on physiology, biochemistry, clinical outcomes, and adverse events, intravenous fluid preparations are like drugs and deserve similar scientific and regulatory scrutiny. When physicians order an infusion of normal saline, Hartmann solution, or 20 percent albumin, these fluids bypass the gut, sometimes overrule the kidney, and reach into the deepest intracellular and interstitial crevices of the body. Clinicians owe it to patients to get intravenous fluid administration right.”

(JAMA. 2012;308[15]:1584-1585. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 16, 2012

Media Advisory: To contact corresponding author Antoni Castells, M.D., Ph.D., email castells@clinic.ub.es. To contact editorial co-author James M. Ford, M.D., call Krista Conger at 650-725-5371 or email kristac@stanford.edu.

CHICAGO – In a comparison of strategies to identify individuals with Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), caused by mutations in certain genes (DNA mismatch repair [MMR] genes), universal tumor MMR testing among certain CRC patients had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the diagnostic improvement was modest, according to a study in the October 17 issue of JAMA.

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related death. “Identification of patients with Lynch syndrome needs to be improved because, unless there is strong clinical suspicion, the majority of cases remain undetected, leading to the lack of implementation of highly effective preventive measures. Indeed, intensive CRC screening by colonoscopy and prophylactic gynecological surgery have been demonstrated to reduce both the incidence and mortality of these tumors,” according to background information in the article. Tumor MMR testing is the cornerstone for identification of Lynch syndrome. “However, it is still under debate which CRC patients should undergo these analyses.”

Leticia Moreira, M.D., of the University of Barcelona, Spain, and colleagues conducted a study to determine a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands (first identified individuals affected with the disorder among other family members). The study consisted of a pooled-data analysis of 4 large groups of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki. The researchers examined personal and family characteristics as well as other tumor and genetic factors and characteristics. Performance characteristics of selected screening strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).

Of 10,206 unrelated CRC probands, 312 (3.1 percent) were MMR gene mutation carriers. The researchers found that universal tumor testing (sensitivity, 100 percent; specificity, 93.0 percent; diagnostic yield, 2.2 percent) was superior to the selective strategy (sensitivity, 95.1 percent; specificity, 95.5 percent; diagnostic yield, 2.1 percent), Bethesda guidelines (sensitivity, 87.8 percent; specificity, 97.5 percent; diagnostic yield, 2.0 percent), and Jerusalem recommendations (sensitivity, 85.4 percent; specificity, 96.7 percent; diagnostic yield, 1.9 percent). “However, differences in diagnostic yield from the universal approach were small, with a difference between universal screening and the next less intensive strategy (i.e., selective strategy) of only 0.11 percent and accompanied by an increase in false-positive yield of 2.5 percent. Indeed, the selective strategy resulted in a 34.8 percent fewer CRC patients requiring tumor MMR testing and an additional 28.6 percent fewer cases undergoing germline MMR mutational analysis in comparison with universal screening.”

“Results of this international, multi-center, pooled-data analysis demonstrate that unless a universal screening approach consisting of tumor MMR testing in all CRC patients is performed, a clinically meaningful proportion of MMR gene mutation carriers will remain undiagnosed. Specifically, use of the revised Bethesda guidelines will miss approximately 12 percent, use of the Jerusalem recommendations will miss approximately 15 percent, and use of a selective criteria [performing tumor MMR testing of CRC probands diagnosed at 70 years or younger or fulfilling 1 or greater criterion of the revised Bethesda guidelines] will miss approximately 5 percent,” the authors write. “These data may be useful to more empirically inform discussions on the most efficient approaches for the identification of Lynch syndrome among CRC probands.”

“Universal tumor screening has, as expected, the highest sensitivity. Although it is not sufficient to just consider sensitivity when comparing different strategies, this is the most important parameter clinically (i.e., to minimize the number of patients with undiagnosed Lynch syndrome). Indeed, it is accepted that the whole Lynch syndrome screening process is cost-effective when the benefits to immediate relatives of identified patients are considered; accordingly, the more patients who are diagnosed, the more at-risk relatives can undergo genetic evaluation and receive appropriate cancer surveillance and other preventive interventions.”

(JAMA. 2012;308[15]:1555-1565. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Lynch Syndrome in Patients With Colorectal Cancer – Finding the Needle in the Haystack

In an accompanying editorial, Uri Ladabaum, M.D., M.S., and James M. Ford, M.D., of the Stanford University School of Medicine, Stanford, Calif., write that “the potential for individualized preventive medicine provides the rationale for screening for Lynch syndrome.”

“In deciding whether to establish widespread screening for Lynch syndrome in selected subgroups, the same considerations that govern screening for CRC in the general population could be applied. The target condition must be common enough to justify screening. A long asymptomatic period must allow for effective interventions. The potential benefits must outweigh the risks. The aggregate costs of screening and its consequences must be acceptable.”

(JAMA. 2012;308[15]:1581-1582. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 16, 2012

Media Advisory: To contact Margaret D. Carroll, M.S.P.H., call Karen Hunter at 404-639-3286 or email ksh7@cdc.gov.

CHICAGO – An analysis of nationally-representative data indicates that between 1988 and 2010 there has been a trend of declining average levels of total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol for U.S. adults overall, according to a study in the October 17 issue of JAMA.

“Epidemiologic studies have demonstrated that high concentrations of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) and low levels of high-density lipoprotein cholesterol (HDL-C) are major risk factors for coronary heart disease (CHD),” according to background information in the article. “Serum total cholesterol and LDL-C contribute to atherosclerosis and its clinical consequences. Between the periods 1988-1994 and 1999-2002, mean [average] TC and mean LDL-C declined in adults. During this time, there was an increase in the percentage of adults receiving lipid-lowering medications.”

Margaret D. Carroll, M.S.P.H., of the Centers for Disease Control and Prevention, Hyattsville, Md., and colleagues conducted a study to examine trends in serum lipids in adults between 1988 and 2010, using three distinct U.S. cross-sectional National Health and Nutrition Examination Surveys, 1988-1994 (n = 16,573), 1999-2002 (n = 9,471), and 2007-2010 (n = 11,766). Included in the analysis were measurements of average levels of TC, LDL-C, HDL-C, non-HDL-C, and geometric triglyceride. The researchers also examined the prevalence of lipid-lowering medication use.

The authors found that average TC declined from 206 mg/dL in 1988-1994 to 203 mg/dL in 1999-2002 and to 196 mg/dL in 2007-2010. Similar trends over this 22-year period were observed in age-adjusted average TC levels for men and for women. From 1988 to 2010, there was a decreasing linear trend in age-adjusted average LDL-C levels for all adults, from 129 mg/dL in 1988-1994 to 123 mg/dL in 1999-2002 and to 116 mg/dL during 2007-2010. “Although men had a higher age-adjusted mean LDL-C level than women during 1988-1994 and 1999-2002, during 2007-2010 there was no longer a sex difference.”

From 1988-1994 to 2007-2010, an increasing linear trend in age-adjusted average HDL-C levels was observed for all adults (50.7 mg/dL vs. 52.5 mg/dL). Between 1988 and 2010, a linear decline in age-adjusted average non-HDL-C level was observed for all adults. The age-adjusted geometric average triglyceride level for all adults increased from 118 mg/dL in 1988-1994 to 123 mg/dL in 1999-2002 and then declined in 2007-2010 to 110 mg/dL.

The researchers also found that from 1988 to 2010, there was an increasing trend in the age-adjusted percentage of adults taking lipid-lowering medications (from 3.4 percent in 1988-1994 to 9.3 percent in 1999-2002 and to 15.5 percent in 2007-2010. Among men and women age 50 years or older, increases in use of lipid-lowering medications of up to 35 percent were observed. “Among adults not receiving lipid-lowering medications, trends in lipids were similar to those reported for adults overall. Among obese adults, mean TC, non-HDL-C, LDL-C, and geometric mean triglycerides declined between 1988 and 2010.”

“The favorable trends in TC, non-HDL-C, and LDL-C may be due in part to a decrease in consumption of trans-fatty acids or other healthy lifestyle changes, in addition to an increase in the percentage of adults taking lipid-lowering medications. They are unlikely to be the result of changes in physical activity, obesity, or intake of saturated fat,” the researchers write. They note that the intake of saturated fat as a percentage of calories did not decrease between 1999 and 2008; little progress was made from 1998 to 2008 in increasing leisure-time physical activity levels of adults; and the prevalence of obesity among adults remains high, at more than one-third of the population. The authors add that “although the percentage of adults receiving lipid-lowering medications continued to increase between 1999-2002 and 2007-2010, declining trends in TC, non-HDL-C, and LDL-C also occurred for adults not taking lipid-lowering medications.”

“Further work is needed to assess simultaneously the effects of trans-fatty acids, lipid-lowering medications, and healthy lifestyle factors on TC, HDL-C, non-HDL-C, LDL-C, and triglycerides.”

(JAMA. 2012;308[15]:1545-1554. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The laboratory analysis of lipids was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this week’s study on trends of cholesterol levels among U.S. adults, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, October 16 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 9, 2012

Study Examines Off-Label Use of Bone Protein For Pediatric Spinal Surgery

Arthrodesis (the surgical fixation of a joint to promote bone fusion) of the spine is frequently performed in children. Although nonunion occurs frequently in adults, children rarely experience nonunion. Bone morphogenetic proteins (BMPs) are approved for limited use in adults when healing may be suboptimal. In addition to concerns about possible carcinogenesis, use of BMPs poses several possible complications. The U.S. Food and Drug Administration has not approved the use of BMPs in children. Emily Dodwell, M.D., M.P.H., of the Hospital for Special Surgery, New York, and colleagues conducted a study to determine the prevalence of BMP use, associated complications, costs, and potential predictors of use in pediatric spinal arthrodesis in the United States.

As reported in a Research Letter, the authors used data from the Kids’ Inpatient Database, Healthcare Cost and Utilization Project, a sample of 4,121 U.S. hospitals, and included children ages 18 years or younger who had undergone primary or revision spine arthrodesis in 2009 (n = 8,289). Nationally, BMP was estimated to be used in 9.2 percent of cases. The estimated prevalence of in-hospital complications in those who received BMP was 3.0 percent and in those who did not receive BMP was 3.6 percent. “Given the lack of indication for augmentation of pediatric spinal arthrodesis, the use of BMP in 9.2 percent of patients is surprising. Although no difference in the rate of in-hospital complications was demonstrated, most complications previously reported with BMP are late complications and would not be expected to occur during hospitalization,” the authors write.  Also, surgeries using BMP were 19 percent more costly than those that did not involve BMP use.

(JAMA. 2012;308[14]:1429-1432. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Computed Tomographic Screening for Lung Cancer – An Opportunity to Evaluate Other Diseases

Onno M. Mets, M.D., of the University Medical Center Utrecht, the Netherlands, and colleagues note that computed tomographic lung cancer screening can provide valuable information that can be used to screen for other diseases, including cardiovascular disease and chronic obstructive pulmonary disease.

“The results of current computed tomography-based lung cancer screening are promising, but the risks associated with cigarette smoking include more than just lung cancer. Because other data are available from lung cancer screening, it is important to discuss how to leverage the additional information for the diagnosis of other diseases, leading to more efficient and effective health care.”

(JAMA. 2012;308[14]:1433-1434. Available pre-embargo to the media at http://media.jamanetwork.com)

The Need for Rigorous Evidence on Medication Use in Preterm Infants – Is It Time for a Neonatal Rule?

Jonathan M. Davis, M.D., of the Floating Hospital for Children at Tufts Medical Center, Boston, and colleagues write that “approximately 200,000 infants born annually in the United States require admission to a neonatal intensive care unit for treatment of prematurity, costing more than $26 billion per year. Preterm infants are at substantial risk of death or developing serious morbidity that can affect them for life. Unlike treatments used in other fields of medicine, most medications administered to preterm infants lack convincing data to support their safety and efficacy with more than 90 percent not approved by the U.S. Food and Drug Administration for the prescribed indication.”

The authors discuss the need for improved research and assessment regarding medications for preterm infants. “Efforts to engage industry leaders in research involving newborns are needed. Industry must accept the need to conduct studies of new and existing agents in the neonatal intensive care unit and develop appropriate formulations for infants and children. Neonatologists should work collaboratively with industry earlier in the drug development process so that simple study designs with easily achievable and validated end points can be achieved.”

(JAMA. 2012;308[14]:1435-1436. Available pre-embargo to the media at http://media.jamanetwork.com)

The FDA Safety and Innovation Act

Robert Steinbrook, M.D., of the Yale School of Medicine, New Haven, Conn., and Joshua M. Sharfstein, M.D., of the Maryland Department of Health and Mental Hygiene, Baltimore, examine the U.S. Food and Drug Administration’s (FDA) Safety and Innovation Act, which reauthorizes for 5 years the collection of user fees from industry for the reviews of prescription drugs and medical devices and establishes new user fee programs for generic drugs and “biosimilar” biological products.

“The overwhelming support in Congress for the Safety and Innovation Act should allow the FDA to continue its work without major disruption. The tasks of the FDA include safety and efficiently helping to bring clinically important products to the bedside and leading efforts to address critical unresolved issues. Unfortunately, the continuing uncertainty over the federal budget may interfere with the agency’s ability to use fees from industry. Congress should specify the FDA’s authority to collect and spend all the user fees authorized by the act, including the new fees for generic drugs and biosimilar biological products. Once the funding is finally in hand, the agency will face the challenge of validating the broad support for the legislation. The FDA’s success in advancing public health will depend on its performance.”

(JAMA. 2012;308[14]:1437-1438. Available pre-embargo to the media at http://media.jamanetwork.com)

Innovations in Care Delivery to Slow Growth of U.S. Health Spending

Arnold Milstein, M.D., M.P.H., of the Stanford University School of Medicine, and Stephen Shortell, Ph.D., M.B.A., M.P.H., of the University of California, Berkeley, write that “the United States needs to slow its rate of growth in inflation-adjusted per capita health spending by 2.5 percentage points annually without sacrificing health or slowing biomedical technology advances. The consequences of failure may include shifting of funding away from resources for elementary and high school education, infrastructure (such as highways), and basic science research, as well as weakening the global competitiveness and financial health of U.S. workers and their employers.”

In this Viewpoint, the authors suggest and discuss four care delivery innovations for helping to address this issue: preventing expensive health crises among medically fragile patients; helping patients in late stages of serious illness avoid dying in a hospital; increasing patient flow through hospitals to lower average fixed cost per hospitalization; and reducing hospital readmissions.

(JAMA. 2012;308[14]:1439-1440. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 9, 2012

Media Advisory: To contact Olle Melander, M.D., Ph.D., email olle.melander@med.lu.se.

CHICAGO – Plasma levels of proneurotensin are associated with the development of diabetes, cardiovascular disease, cardiovascular and total mortality, and breast cancer in women during long-term follow-up, according to a study in the October 10 issue of JAMA.

Neurotensin, an amino acid peptide primarily expressed in the central nervous system and gastrointestinal tract, regulates both satiety and breast cancer growth in the experimental setting, but little is known about its role in the development of breast cancer or cardiometabolic disease in humans, according to background information in the article. Proneurotensin is a precursor of the hormone neurotensin.

Olle Melander, M.D., Ph.D., of Lund University, Malmo, Sweden and colleagues conducted a study to test if a fasting plasma concentration of proneurotensin is associated with future risk of diabetes mellitus, cardiovascular disease, breast cancer, and death. Proneurotensin was measured in plasma from 4,632 fasting participants of the population-based Malmo Diet and Cancer Study baseline examination 1991-1994. Various models were used to evaluate the relationship between baseline proneurotensin and first events and death during long-term follow-up until January 2009, with median (midpoint) follow-up ranging from 13.2 to 15.7 years depending on the disease.

Overall, proneurotensin was related to risk of new diabetes, cardiovascular disease, and cardiovascular mortality, with a significant interaction between proneurotensin and sex on risk of cardiovascular disease. “Exclusively in women, proneurotensin was related to incident diabetes, cardiovascular disease, breast cancer, total mortality, and cardiovascular mortality,” the authors write.

The researchers note that the elevation of proneurotensin several years before onset of disease indicates that proneurotensin may be a marker of underlying disease susceptibility rather than an expression of subclinical disease. “As an observational study, our results do not prove any causation between proneurotensin and cardiometabolic disease and breast cancer.”

The authors add that the relationships between proneurotensin and all end points were significant in women but not in men; however, because there was only significant interaction between sex and proneurotensin for the outcome of incident cardiovascular disease, it remains to be shown whether the association between proneurotensin and adverse outcome is specific for women.

(JAMA. 2012;308[14]:1469-1475. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 9, 2012

Media Advisory: To contact Karen E. Joynt, M.D., M.P.H., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.  To contact editorial author Maura Moscucci, M.D., M.B.A., call Lisa Worley at 305-243-5184 or email lworley2@med.miami.edu.

CHICAGO – In an analysis that included nearly 100,000 Medicare patients who had experienced a heart attack, the use of a percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries) was lower for patients treated in states with public reporting of PCI outcomes compared with patients treated in states without public reporting, with these differences being particularly large in the highest-risk patients, according to a study in the October 10 issue of JAMA. However, the researchers found that there was no difference in overall heart attack survival rates between states with and without public reporting.

“Public reporting of patient outcomes is a key tool to drive improvements in health care delivery. Over the past 20 years, three states—New York (1991), Pennsylvania (2001), and Massachusetts (2005)—have instituted mandatory public reporting of outcomes for PCI. The idea behind public reporting is simple: collecting and publicly reporting performance will enable patients to choose high-quality hospitals and motivate clinicians to improve performance. However, critics worry that public reporting may create disincentives for physicians and hospitals to care for the sickest patients, potentially leading clinicians to avoid offering lifesaving procedures to these patients,” according to background information in the article.

Karen E. Joynt, M.D., M.P.H., of the Harvard School of Public Health, Boston, and colleagues conducted a study to determine whether public reporting for PCI is associated with lower rates of PCI for patients with acute myocardial infarction (MI; heart attack) or with higher mortality rates in this population. The study was conducted using data from fee-for-service Medicare patients (49,660 from reporting states and 48,142 from nonreporting states) admitted with acute MI to U.S. acute care hospitals between 2002 and 2010. Analysis compared PCI and mortality rates between reporting states (New York, Massachusetts, and Pennsylvania) and regional non-reporting states (Maine, Vermont, New Hampshire, Connecticut, Rhode Island, Maryland, and Delaware). Changes in PCI rates over time in Massachusetts also were compared with rates in nonreporting states.

The researchers found that among patients admitted for an acute MI in 2010, those in public reporting states were significantly less likely to receive a PCI compared with the regional control group of patients in nonreporting states (unadjusted rates, 37.7 percent vs. 42.7 percent).  “This was most pronounced in the ST-segment elevation myocardial infarction [STEMI; a certain pattern on an electrocardiogram following a heart attack] and the cardiogenic shock or cardiac arrest groups. The odds of receiving a PCI for patients in the non-ST-segment elevation myocardial infarction [NSTEMI; a type of heart attack with certain findings on an electrocardiogram] group in public reporting states vs. nonreporting states were similar (30.3 percent vs. 33.7 percent), whereas for the STEMI group (61.8 percent vs. 68.0 percent) and the cardiogenic shock or cardiac arrest group (41.5 percent vs. 46.7 percent), the odds were significantly lower. These differences were similar in the older (75 years or older) age group.”

The authors also examined changes in PCI rates in Massachusetts, a state that initiated public reporting for PCI in the recent era. “In the pre-reporting period, patients in Massachusetts were similarly likely to undergo PCI when compared with patients in non-reporting states (unadjusted rates, 40.6 percent vs. 41.8 percent). However, by the postreporting period, the odds of receiving PCI had decreased in Massachusetts relative to nonreporting states (41.1 percent vs. 45.6 percent).” Differences were most pronounced for the 6,081 patients with cardiogenic shock or cardiac arrest (pre-reporting: 44.2 percent vs. 36.6 percent; postreporting: 43.9 percent vs. 44.8 percent).

The researchers also found no overall difference in 30-day mortality among patients with acute MI in public reporting vs. nonreporting states (unadjusted rates, 12.8 percent vs. 12.1 percent). Mortality was higher in the STEMI subgroup (13.5 percent vs. 11.0 percent).

The authors write that there are at least 2 possible explanations for why public reporting was associated with lower rates of PCI for patients admitted for an acute MI. “It is possible that many of the foregone procedures were futile or unnecessary, and public reporting focused clinicians on ensuring that only the most appropriate procedures were performed. Alternatively, public reporting may have led clinicians to avoid PCI in eligible patients because of concern over the risk of poor outcomes. Although policy makers have made efforts to ensure that risk adjustment models account for patient complexity, prior qualitative work suggests that clinicians remain concerned about receiving adequate ‘credit’ for the comorbid conditions of their own patient population. Our data cannot definitively differentiate between these 2 potential mechanisms.”

“Strategies to help clinicians differentiate between patients likely to benefit from PCI and those for whom it would be futile are critically important. Promising work in this area is already underway. Providing real-time models of both risk and benefit may help physicians, patients, and families make more informed decisions about when to pursue PCI. Similarly, strategies to provide adequate credit for taking care of the sickest patients would also be useful.”

(JAMA. 2012;308[14]:1460-1468. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Funding for this study was provided by a grant from the National Heart, Lung, and Blood Institute. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, October 9 at this link.

Editorial: Public Reporting of PCI Outcomes and Quality of Care – One Step Forward and New Questions Raised

Maura Moscucci, M.D., M.B.A., of the University of Miami Miller School of Medicine, comments on the findings of this study in an accompanying editorial.

“Patients are often treated regardless of the perceived futility of the planned intervention. The study by Joynt et al confirms the possible unintended consequences of public reporting, while highlighting its association with (or lack of association with) clinical outcomes. In addition, these findings may help spearhead a new focus on procedures that, while perceived appropriate based on current use criteria, might not result in added benefit in selected patients.”

(JAMA. 2012;308[14]:1478-1479. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 9, 2012

Media Advisory: To contact Carolyn R. Broderick, M.B.B.S., email c.broderick@unsw.edu.au. To contact Marilyn J. Manco-Johnson, M.D., call Jacque Montgomery at 303-928-9093 or email Jacque.Montgomery@ucdenver.edu.

CHICAGO – In children and adolescents with hemophilia, vigorous physical activity was associated with an elevated risk of bleeding, although it appears the absolute increase in risk may be small, according to a study in the October 10 issue of JAMA.

Hemophilia is a bleeding disorder that, if untreated, causes recurrent bleeding into joints. “Vigorous physical activity is thought to increase risk of bleeds in children with hemophilia, but the magnitude of the risk is unknown,” according to background information in the article. Information about risks associated with physical activity is needed to help inform decisions regarding participation in physical activity, the authors write.

Carolyn R. Broderick, M.B.B.S., of the University of Sydney, Australia and colleagues conducted a study to quantify the transient (short duration) increase in risk of bleeding associated with vigorous physical activity in children with hemophilia. The study was conducted at three pediatric hemophilia centers in Australia between July 2008 and October 2010 and included 104 children and adolescent boys ages 4 through 18 years with moderate or severe hemophilia A or B who were monitored for bleeds for up to 1 year. Following each bleed, the child or parent was interviewed to determine exposures to physical activity preceding the bleed. Physical activity was categorized according to expected frequency and severity of collisions. The risk of bleeds associated with physical activity was estimated by contrasting exposure to physical activity in the 8 hours before the bleed with exposures in two 8-hour control (non-bleed) windows, controlling for levels of clotting factor in the blood. The median (midpoint) duration of follow-up was 52 weeks.

There were 436 bleeds, of which 336 were study bleeds (i.e., bleeding episodes without another bleeding episode in the preceding 2 weeks). Eighty-eight participants (84 percent) reported at least 1 bleed. The most frequent sites of bleeding were the knee (15 percent), ankle (14 percent), and elbow (10 percent). Compared with inactivity and category 1 activities (e.g., swimming), category 2 activities (e.g., basketball) were associated with a transient increase in the risk of bleeding (30.6 percent of bleed windows vs. 24.8 percent of first control windows; odds ratio, 2.7). Category 3 activities (e.g., wrestling) were associated with a greater transient increase in risk (7.0 percent of bleed windows vs. 3.4 percent of first control windows; odds ratio, 3.7). These odds of bleeding suggest that for most children, the absolute increase in risk associated with physical activity is low. “To illustrate absolute risk increase, for a child who bleeds 5 times annually and is exposed on average to category 2 activities twice weekly and to category 3 activities once weekly, exposure to these activities was associated with only 1 of the 5 annual bleeds,” the authors write. Most bleeds associated with physical activity were present within an hour of activity.

“This study confirms that physical activity is associated with an increased risk of bleeds in children and adolescents with moderate or severe hemophilia A or B. It demonstrates that the relative increase in risk is moderate. However, for most children, the absolute increase in risk is likely to be low,” the researchers conclude.

(JAMA. 2012;308[14]:1452-1459. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was supported by a project grant from the National Health and Medical Research Council (NHMRC). Dr. Herbert is supported by a research fellowship from the Australian NHMRC, and Dr. Latimer is supported by a Future Fellowship from the Australian Research Council. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Collision Sports and Risk of Bleeding in Children With Hemophilia

Marilyn J. Manco-Johnson, M.D., of the University of Colorado and Children’s Hospital Colorado, Aurora, writes in an accompanying editorial that participation in sports can be important to help reduce the sense of isolation experienced by many children with hemophilia, and that “guidelines focused on children with hemophilia and participation in collision sports are needed.”

“These recommendations should include educating parents and athletes about potential short and long complications related to sports participation, risk reduction measures with prophylaxis regimens, conditioning and strengthening programs, and the healthful contributions of sports participation toward physical, social, and emotional development as well as the prevention of obesity.”

(JAMA. 2012;308[14]:1480-1481. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported having received honoraria for advisory board participation from Baxter Bioscience, Bayer HealthCare, CSL Behring, NovoNordisk, and Octapharma and having received research funding from Bayer Healthcare and CSL Behring.

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EMBARGOED FOR EARLY RELEASE: 8 A.M. (CT) MONDAY, OCTOBER 8, 2012

Media Advisory: To contact Dean A. Fergusson, M.H.A., Ph.D., call Paddy Moore at 613-737-8899, ext. 73687, or email padmoore@ohri.ca.

CHICAGO – Among premature, very low-birth-weight infants requiring a transfusion, use of fresh red blood cells (RBCs) compared with standard RBC transfusion practice did not improve clinical outcomes that included rates of complications or death, according to a study in the October 10 issue of JAMA. The study is being published early online to coincide with its presentation at the AABB (formerly the American Association of Blood Banks) Annual Meeting.

“Although RBC transfusions are used routinely in acutely ill patients, including those in neonatal intensive care units, the clinical consequences of the prolonged storage of RBCs have not been firmly established,” according to background information in the article. “In recent years, several observational studies conducted primarily in adults have demonstrated that prolonged RBC storage is associated with increased rates of infection, organ failure, death, and increased lengths of stay.”

Dean A. Fergusson, M.H.A., Ph.D., of the Ottawa Hospital Research Institute, Ottawa, Canada and colleagues conducted a study to evaluate whether RBCs stored for 7 days or less decreased serious neonatal illness and death compared with standard blood bank issue. The randomized controlled trial included 377 premature infants with birth weights less than 2.8 lbs. (1,250 grams) admitted to 6 Canadian neonatal intensive care units between May 2006 and June 2011. Patients were randomly assigned to receive transfusion of RBCs stored 7 days or less (n = 188) vs. standard-issue RBCs in accordance with standard blood bank practice (n = 189). The primary outcome for the study was a composite measure of major neonatal illnesses, as well as death. The primary outcome was measured within the entire period of neonatal intensive care unit stay up to 90 days after randomization. The rate of hospital-acquired (nosocomial) infection was a secondary outcome.

The average age of blood in the fresh RBC group was 5.1 days, compared with 14.6 in the standard RBC group. The average and median (midpoint) volumes transfused were similar in both groups, as were postrandomization cointerventions including modes of ventilation, insertion of lines and catheters, other blood products, and major surgical and diagnostic procedures.

A total of 199 infants (53.0 percent) experienced the composite primary outcome. The researchers found that among infants in the fresh RBC group, 99 (52.7 percent) had the primary outcome compared with 100 (52.9 percent) in the standard RBC group. “The rate of clinically suspected infection in the fresh RBC group was 77.7 percent (n = 146) vs. 77.2 percent (n = 146) in the standard RBC group. Rates of confirmed infections were 67.5 percent (n = 127) in the fresh RBC group vs. 64.0 percent (n = 121) in the standard RBC group. Among confirmed cases, rates of bacterial, fungal, and viral infections were similar between the 2 groups.  Major sequelae of infections including rates of pneumonia, meningitis and osteomyelitis [inflammation of bone or bone marrow, usually due to infection] were also similar. The median (midpoint) length of neonatal intensive care unit stay was 77 days in the standard RBC group and 84 days in the fresh RBC group.”

“We did not find any clinically meaningful or statistically significant differences and, therefore, the many laboratory changes that occur with prolonged RBC storage may not be as important as once thought,” the authors write.

“In conclusion, the transfusion of fresh RBCs did not improve clinical outcomes in high-risk, premature, very low-birth-weight infants. We thus do not recommend any changes to storage time practices for the provision of RBCs to infants admitted to neonatal intensive care.”

(JAMA. 2012;308[14]:1443-1451. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Funding for this study was provided by the Canadian Institutes for Health Research. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 2, 2012

Challenges at the Intersection of Team-Based and Patient-Centered Health Care – Insights From an IOM Working Group

Matthew K. Wynia, M.D., M.P.H., of the American Medical Association, Chicago, and colleagues write that team-based health care may help the United States achieve improved health and improved health care at a sustainable cost.  “Team-based care can occur in many settings (e.g., home, office, hospital); focus on different problems (e.g., specific diseases); and include team members with a variety of backgrounds.” In this Viewpoint, the authors examine some of the challenges presented by team-based care.

“Implementing patient-centered, team-based care requires overcoming several challenges, but health care that meets the promise of ‘nothing about me without me’ is worth pursuing. Bringing patients into the orchestra of team-based care requires not only new skills and tools but wholly reframing how clinicians and patients view roles (including leadership) and accountability—even the language describing the care patients ‘receive’ and other team members ‘provide’.”

(JAMA. 2012;308[13]:1327-1328. Available pre-embargo to the media at http://media.jamanetwork.com)

A New Model for Medical Education – Celebrating Restraint

Allan S. Detsky, M.D., Ph.D., and Amol A. Verma, M.D., M.Phil., of the University of Toronto, “suggest complementing health care cost control initiatives by transforming the current approach used in medical education that primarily rewards meticulousness of clinical investigation to one that also celebrates appropriate restraint.”

“The current system of medical education that emphasizes mentorship puts the attending physician in a remarkably powerful position of influence over the future practice of medical students and trainees. All practicing physicians find themselves falling back on strategies they learned from observing their clinical teachers and asking, ‘What would the attending who supervised my learning as a clinical clerk or resident do with this patient?’ Policy makers should engage medical educators to harness that power to disseminate the practice of restraint as part of cost-control efforts in the future.”

(JAMA. 2012;308[13]:1329-1330. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 2, 2012

Media Advisory: To contact corresponding author Richard J. Barohn, M.D., call C.J. Janovy at 913-588-2598 or email cjanovy@kumc.edu. To contact editorial co-author Eric P. Hoffman, Ph.D., call Paula Darte at 202-821-6357 or email pdarte@ChildrensNational.org.

CHICAGO – Preliminary research finds that for patients with nondystrophic myotonias (NDMs), rare diseases that affect the skeletal muscle and cause functionally limiting stiffness and pain, use of the anti-arrhythmic medication mexiletine resulted in improvement in patient-reported stiffness, according to a preliminary study in the October 3 issue of JAMA.

Data on treatment of NDMs are largely anecdotal, consisting of case series and a single-blind, controlled trials of several medications including mexiletine, according to background information in the article.

Jeffrey M. Statland, M.D., of the University of Rochester Medical Center, Rochester, New York, and colleagues in the Consortium for Clinical Investigation of Neurologic Channelopathies conducted a study to determine the effects of mexiletine for symptoms and signs of myotonia (prolonged failure of muscle relaxation after contraction) in patients with NDMs. The randomized study, part of the National Institutes of Health-funded Rare Disease Clinical Research Network, was conducted at seven neuromuscular referral centers in four countries between December 2008 and March 2011 and included 59 patients with NDMs. Patients (33 men, 26 women; average age, 43 years) received either oral 200-mg mexiletine or placebo capsules three times daily for four weeks, followed by the opposite intervention for four weeks, with 1-week washout in between. The main outcome measured for the study was patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary outcomes included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact).

Data from 57 participants who made telephone calls to the IVR diary in weeks 3 to 4 of period 1 or 2 were included in the analysis. The researchers found that mexiletine was associated with significantly improved stiffness as reported on the IVR diary in both treatment periods. For period 1, the treatment effect was 2.53 for mexiletine vs. 4.21 for placebo; for period 2, 1.60 for mexiletine vs. 5.27 for placebo.

There were significant improvements with mexiletine in most other outcomes in the study, including patient-reported outcomes, quality of life scales, and quantitative measures of myotonia (improved myotonia as measured on clinical examination by overall handgrip times in seconds).

“The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related,” the authors write.

“Our study provides preliminary evidence of the effectiveness of mexiletine for symptoms and signs of myotonia in NDMs,” the researchers write. “The clinical significance of the improvement in stiffness score on the IVR diary is supported by the broad improvement in clinical, quantitative, and electrophysiological measures of myotonia.”

(JAMA. 2012;308[13]:1357-1365. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Mexiletine for Treatment of Myotonia – A Trial Triumph for Rare Disease Networks

“The study by Statland et al provides important information that should help inform the treatment of patients with myotonia,” writes Eric P. Hoffman, Ph.D., of the Children’s National Medical Center, and Henry J. Kaminski, M.D., of George Washington University, Washington, D.C., in an accompanying editorial.

“The success of this trial should encourage the Consortium for Clinical Investigation of Neurologic Channelopathies (CCINC) group to take the lead with larger phase 3 trials. Even more exciting would be development of novel agents that can produce therapeutic benefit with much greater effect sizes. Most important, the National Institutes of Health, industry, and patient advocacy groups should attempt to replicate the success of the CCINC through establishment of more clinical research consortia focused on rare disorders.”

(JAMA. 2012;308[13]:1377-1378. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 2, 2012

Media Advisory: To contact Marie E. Holmqvist, M.D., Ph.D., email marie.holmqvist@ki.se.

CHICAGO – A study that included more than 45,000 residents of Sweden with rheumatoid arthritis finds that individuals with this disease had an associated higher risk of venous thromboembolism (a blood clot that forms within a vein), and that this elevated risk was stable for 10 years after the time of diagnosis, according to a study in the October 3 issue of JAMA.

“Recent reports suggest that rheumatoid arthritis (RA) may be a risk factor for venous thromboembolism (VTE), particularly in conjunction with hospitalization. Using hospitalization data to identify RA and VTE may identify patients when they are at elevated risk for other reasons, obscuring the incompletely understood underlying association between RA and VTE and leading to inappropriate institution or timing of interventions,” according to background information in the article.

Marie E. Holmqvist, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden and colleagues conducted a study to assess the overall occurrence and relative risks of VTE in patients with RA in relation to RA onset and disease duration as well as in conjunction with hospitalization. The study included a prevalent RA group (n = 37,856), an incident RA group (n = 7,904), and matched general population comparison groups, all from Sweden, with follow-up from 1997 through 2010.

Of the patients with prevalent RA and the matched individuals in the general population comparison cohort, 838 patients (2.2 percent) and 1,866 matched individuals (1.1 percent) had a VTE event after the index date, with analysis of the data indicating that patients with prevalent RA were at greater risk of VTE than the general population. There was no statistically significant association between a history of VTE and RA by the time of RA symptom onset. Counting from RA diagnosis, an increased rate in the RA cohort vs. the comparison cohort was detected within the first year and did not increase further during the first decade. The researchers also found that although rates for VTE following hospitalization were higher, the 1-year rate of VTE was not higher in the RA cohort than in the comparison cohort after hospital discharge. The rates of VTE increased with age but were largely similar across sex and rheumatoid factor status.

“The results of this study suggest that patients with RA are at increased risk of VTE (both deep vein thrombosis and pulmonary embolism) and that the risk of VTE increases shortly after RA diagnosis and remains similarly elevated during the first decade,” the authors write.

“Hospitalization is a strong risk factor for VTE in the general population and in patients with RA, but the short-term (<1 year after hospital discharge) rates for VTE are similar in both groups. VTE rates varied with age, less so with sex, calendar period of RA diagnosis, and rheumatoid factor status, but the relative risks of VTE were largely similar across these patient subgroups.”

(JAMA. 2012;308[13]:1350-1356. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This research was funded by the Swedish Research Council, Swedish program on Chronic inflammation (Combine), and Swedish Foundation for Strategic Research. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 2, 2012

Media Advisory: To contact Sripal Bangalore, M.D., M.H.A., call Allison Clair at 212-404-3753 or email allison.clair@nyumc.org.

CHICAGO – Among patients with either coronary artery disease (CAD) risk factors only, known prior heart attack, or known CAD without heart attack, the use of beta-blockers was not associated with a lower risk of a composite of cardiovascular events that included cardiovascular death, nonfatal heart attack or nonfatal stroke, according to a study in the October 3 issue of JAMA.

“Treatment with beta-blockers remains the standard of care for patients with coronary artery disease, especially when they have had a myocardial infarction [MI; heart attack]. The evidence is derived from relatively old post-MI studies, most of which antedate modern reperfusion or medical therapy, and from heart failure trials, but has been widely extrapolated to patients with CAD and even to patients at high risk for but without established CAD. It is not known if these extrapolations are justified. Moreover, the long-term efficacy of these agents in patients treated with contemporary medical therapies is not known, even in patients with prior MI,” according to background information in the article.

Sripal Bangalore, M.D., M.H.A., of the NYU School of Medicine, New York, and colleagues conducted a study to evaluate the association between beta-blocker use and long-term cardiovascular outcomes. The observational study included data from patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry. From this registry, 44,708 patients met the study inclusion criteria of whom 14,043 patients (31 percent) had prior MI, 12,012 patients (27 percent) had documented CAD but without MI, and 18,653 patients (42 percent) had CAD risk factors only. The last follow-up data collection was April 2009. The primary outcome for this study was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure. The overall median (midpoint) follow-up was 44 months. Among the 44,708 patients in the study, 21,860 were included in the propensity score-matched analysis.

The researchers found that in the prior MI group, the event rates were not significantly different among those with beta-blocker use (489 [16.93 percent]) vs. those without beta-blocker use (532 [18.60 percent]) for the primary outcome, or the secondary outcome (30.96 percent vs. 33.12 percent, respectively). In the CAD without MI cohort, the event rates were not different in those with beta-blocker use (391 [12.94 percent]) vs. those without p-blocker use (405 [13.55 percent]) for the primary outcome, for cardiovascular death, for stroke, and for MI.  The event rates were higher in those with beta-blocker use (1,101 [30.59 percent] vs. those without beta-blocker use (1,002 [27.84 percent]) for the secondary outcome and for hospitalization in the propensity score-matched model.

In the risk factors alone group, the event rates were higher in those with beta-blocker use (467 [14.22 percent] vs. those without beta-blocker use (403 [12.11 percent]) for the primary outcome, for the secondary outcome (870 [22.01 percent] vs. 797 [20.17 percent], respectively) but not for MI or stroke. In the propensity score-matched model, there were similar event rates for cardiovascular death and for hospitalization.

The researchers also found that among patients with recent MI (one year or less), beta-blocker use was associated with a lower incidence of the secondary outcome.

“Among patients enrolled in the international REACH registry, beta-blocker use was not associated with a lower event rate of cardiovascular events at 44-month follow-up, even among patients with prior history of MI. Further research is warranted to identify subgroups that benefit from beta-blocker therapy and the optimal duration of beta-blocker therapy,” the authors conclude.

(JAMA. 2012;308[13]:1340-1349. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 2, 2012

Media Advisory: To contact David R. Murdoch, M.D., email david.murdoch@otago.ac.nz. To contact editorial author Jeffrey A. Linder, M.D., M.P.H., call Marjorie Montemayor-Quellenberg at 617-534-2208 or email mmontemayor-quellenberg@partners.org.

CHICAGO – Although some data have suggested a possible inverse association between serum vitamin D levels and the incidence of upper respiratory tract infections (colds), participants in a randomized controlled trial who received a monthly dose of 100,000 IUs of vitamin D₃ did not have a significantly reduced incidence or severity of colds, according to a study in the October 3 issue of JAMA.

The association of vitamin D insufficiency and susceptibility to viral respiratory tract infections has been unclear, according to background information in the article.

David R. Murdoch, M.D., of the University of Otago, Christchurch, New Zealand, and colleagues conducted a randomized trial to examine the effect of vitamin D supplementation on incidence and severity of upper respiratory tract infections (URTIs) in healthy adults. The study, conducted between February 2010 and November 2011, included 322 healthy adults in New Zealand. Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D₃, then 200,000 IU one month later, then 100,000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months.

The average 25-hydroxyvitamin D (25-OHD) level of participants at the beginning of the study was 29 ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group.

The researchers found that there was no statistically significant differences in the number of URTIs per participant (average, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group), duration of symptoms per episode (average, 12 days in each group), number of days of missed work as a result of URTIs, or severity of URTI episodes.

“The main finding from this study is that a monthly dose of 100,000 IU of vitamin D₃ in healthy adults did not significantly reduce the incidence or severity of URTIs. This result remained unchanged when the analysis included winter season or baseline 25-OHD levels,” the authors write. “Further research is required to clarify whether there is benefit from supplementation in other populations and with other dosing regimens.”

(JAMA. 2012;308[13]:1333-1339. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The study was funded by the Health Research Council of New Zealand. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, October 2 at this link.

Editorial: Vitamin D and the Cure for the Common Cold

Jeffrey A. Linder, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, comments on the findings of this study (VIDARIS ) in an accompanying editorial.

“The 2011 IOM report called for additional research to determine whether vitamin D therapy reduces the incidence of respiratory tract infections. The VIDARIS trial has rigorously addressed this question. Results suggest that vitamin D should join the therapies listed in the Cochrane reviews as being ineffective for preventing or treating upper respiratory tract infections in healthy adults.”

(JAMA. 2012;308[13]:1375-1376. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Dr. Linder’s work on acute respiratory tract infections is supported by grants from the National Institutes of Health, the National Institute of Allergy and infectious Diseases, and the Agency for Healthcare Research and Quality. The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 25, 2012

Bringing Diagnosis Into the Quality and Safety Equations

Mark L. Graber, M.D., of RTI International, St. James, N.Y., and colleagues suggest that cases of delayed, missed and incorrect diagnosis are common, with an incidence in the range of 10 percent to 20 percent, and that in a recent survey of more than 6,000 physicians, 96 percent felt that diagnostic errors were preventable. “How is it then that improving diagnosis goes largely unrepresented in the current quality framework?”

In this Viewpoint, the authors discuss the importance of integrating diagnosis into quality and safety measures. “The centuries-old debate over whether diagnosis or treatment is more important cannot ever be answered, but no one debates that the right treatment depends on the correct diagnosis. The time has come for the health care quality and safety communities to give these twin pillars of medical care equal consideration in matters of training, research, and policy.”

(JAMA. 2012;308[12]:1211-1212. Available pre-embargo to the media at http://media.jamanetwork.com)

Overcoming the Pricing Power of Hospitals

Bob Kocher, M.D., of Venrock, Palo Alto, Calif., and Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, describe the effects of aggressive price increases by hospitals, and suggest steps to reduce hospital market power.

“The first step on the transformation pathway is to adopt policies that create the right incentives. The 3 proposed changes of incentivizing physicians, supporting pricing transparency, and reforming local markets (with the exception of prohibiting gag rules) can largely be done without new legislation.”

(JAMA. 2012;308[12]:1213-1214. Available pre-embargo to the media at http://media.jamanetwork.com)

Beyond Joint Implant Registries – A Patient-Centered Research Consortium for Comparative Effectiveness in Total Joint Replacement

Patricia D. Franklin, M.D., M.P.H., M.B.A., of the University of Massachusetts Medical School, Worcester, and colleagues point out that “despite the proven effectiveness of total joint replacement (TJR) surgery in relieving advanced knee and hip arthritis pain, TJR outcomes have come under intense public scrutiny in recent years. The 2010 recall of ASR metal-on-metal hip implants heightened awareness of the importance for implant safety surveillance for this high-cost and high-use procedure and exposed the need for a national systematic patient-centered outcomes monitoring system.”

To address this need, the Agency for Healthcare Research and Quality funded a 4-year $12 million research program, Function and Outcomes Research for Comparative Effectiveness in TJR (FORCE-TJR), which will generate comparative effectiveness research. In this Viewpoint, the authors discuss the objectives and potential usefulness of this program in guiding the decisions of clinicians and patients regarding total joint replacement.

(JAMA. 2012;308[12]:1217-1218. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 25, 2012

Media Advisory: To contact corresponding author Christopher J. Hartnick, M.D., call Mary Leach at 617-573-4170 or email Mary_Leach@meei.harvard.edu.

CHICAGO – Administration of the corticosteroid dexamethasone to children during a tonsillectomy was not associated with excessive, serious bleeding events following surgery compared to patients who received placebo, according to a study in the September 26 issue of JAMA.

Tonsillectomy is exceedingly common, with a reported increase in tonsillectomy rates in children younger than 15 years from 287,000 to 530,000 per year over the past decade. Although safe, adenotonsillectomy can result in significant complications, according to background information in the article. “Although complications are infrequent because tonsillectomy is so common, the absolute number of children experiencing tonsillectomy complications is formidable.” Corticosteroids are often given to children undergoing tonsillectomy to reduce postoperative nausea and vomiting; however, previous research has suggested that corticosteroids may increase the risk of hemorrhage during and after surgery.

“A recent randomized trial studying the dose response of perioperative dexamethasone to postoperative nausea and vomiting [PONV] in children undergoing tonsillectomy was prematurely terminated due to an increased risk of postoperative hemorrhage. The outcomes of the trial suggested that a single dose of intraoperative dexamethasone significantly increased post-tonsillectomy hemorrhage events. In light of these findings, there is a need to reassess the safety profile for dexamethasone when used during tonsillectomy,” the authors write.

Thomas Q. Gallagher, M.C., U.S.N., of the Naval Medical Center Portsmouth, Va., and colleagues performed a clinical trial to examine bleeding events in children associated with dexamethasone use during tonsillectomy. The multicenter, randomized trial included 314 children ages 3 to 18 years undergoing tonsillectomy without a history of bleeding disorder or recent corticosteroid medication use. The study was conducted between July 2010 and December 2011 with 14-day follow-up. The researchers tested the hypothesis that dexamethasone would not result in 5 percent more bleeding events than placebo using a noninferiority (outcome not worse than treatment compared to) statistical design. Patients received a single perioperative dose of dexamethasone or an equivalent volume of saline.

The primary outcome measured was rate and severity of post-tonsillectomy hemorrhage in the 14-day postoperative period using a bleeding severity scale (level I, self-reported or parent-reported postoperative bleeding; level II, required inpatient admission for postoperative bleeding; or level III, required reoperation to control postoperative bleeding).

One hundred fifty-seven children (median [midpoint] age, 6 years) were randomized into each study group, with 17 patients (10.8 percent) in the dexamethasone group and 13 patients (8.2 percent) in the placebo group reporting bleeding events. The overall rate of bleeding events for all levels was 30 out of 314 (9.6 percent). The researchers found that in an intention-to-treat analysis, the rates of level I bleeding were 7.0 percent (n = 11) in the dexamethasone group and 4.5 percent (n = 7) in the placebo group; rates of level II bleeding were 1.9 percent (n = 3) and 3.2 percent (n = 5), respectively; and rates of level III bleeding were 1.9 percent (n = 3) and 0.6 percent (n = 1), respectively.

“The dexamethasone treatment failed to show noninferiority for the level I bleeding, but did demonstrate that the bleeding rate with dexamethasone is not more than 5 percent greater than that with placebo (noninferiority) for both level II and III bleeding events. The data was stratified for primary vs. secondary bleeding events and a decrease in level II and level III bleeding events in both groups was noted,” the authors write.

“In conclusion, in this prospective, randomized study of 314 children undergoing tonsillectomy, perioperative dexamethasone administration was not associated with more level II or III bleeding events than placebo as shown by noninferiority. Increased subjective (level 1) bleeding events caused by dexamethasone could not be excluded because the noninferiority threshold of 5 percent was crossed,” the authors write.

(JAMA. 2012;308[12]:1221-1226. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 25, 2012

Media Advisory: To contact Peter Cram, M.D., M.B.A., call Tom Moore at 319-356-3945 or email thomas-moore@uiowa.edu. To contact editorial co-author Joseph D. Zuckerman, M.D., call Craig Andrews at 212-404-3511 or email Craig.Andrews@nyumc.org.

CHICAGO – There has been an increase in total knee arthroplasty (TKA; knee replacement) procedures over the past 20 years that has been driven by both an increase in the number of Medicare enrollees and increase in per capita utilization, according to a study in the September 26 issue of JAMA. There has also been a decrease in hospital length of stay for TKA, but increased hospital readmission rates and increased rates of infectious complications.

“Total knee arthroplasty is a common and safe procedure typically performed for relief of symptoms in patients with severe knee arthritis. Available data suggest that approximately 600,000 TKA procedures are performed annually in the United States at a cost of approximately $15,000 per procedure ($9 billion per year in aggregate),” according to background information in the article. Total knee arthroplasty is one of the most common and costly surgical procedures performed in the United States. “Despite the clinical and economic policy importance of TKA, there are few analyses evaluating recent trends over time in use of and outcomes associated with TKA.”

Peter Cram, M.D., M.B.A., of the University of Iowa Carver College of Medicine, Iowa City, Iowa, and colleagues conducted a study to evaluate trends in primary and revision TKA volume, per capita utilization, and outcomes in the U.S. Medicare population for the time period between 1991 and 2010. The analysis included 3,271,851 patients (age 65 years or older) who underwent primary TKA and 318,563 who underwent revision TKA identified in Medicare Part A data files.

The researchers found that the number of primary TKA procedures increased from 93,230 in 1991 to 243,802 in 2010 (an increase of 161.5 percent), while per capita utilization increased 99.2% (from 31.2 procedures per 10,000 Medicare enrollees in 1991 to 62.1 procedures per10,000 in 2010). The number of revision TKA procedures increased from 9,650 in 1991 to 19,871 in 2010 (an increase of 105.9 percent), and per capita utilization increased 59.4 percent (from 3.2 procedures per 10,000 Medicare enrollees in 1991 to 5.1 procedures per 10,000 in 2010). Also during this time period, the prevalence of obesity among patients undergoing primary TKA increased from 4.0 percent to 11.5 percent. The average hospital length of stay (LOS) for primary TKA declined from 7.9 days in 1991-1994 to 3.5 days in 2007-2010, a relative decline of 55.7 percent. All-cause 30-day readmission rates increased from 4.2 percent in 1991-1994 to 5.0 percent in 2007-2010.

“Trends in discharge disposition after revision TKA demonstrated a similar pattern to that which was observed for primary TKA, a decline in discharges to home or inpatient rehabilitation and an increase in discharge to skilled care and outpatient rehabilitation,” the authors write.

The researchers add that for revision TKA, a decrease in hospital LOS was accompanied by an increase in all-cause 30-day readmission from 6.1 percent to 8.9 percent and an increase in readmission for wound infection from 1.4 percent to 3.0 percent.

“These figures suggest that growth in primary and revision TKA volume is being driven by both an increase in the number of Medicare enrollees and an increase in per capita arthroplasty utilization,” the authors write. “This growth is likely driven by a combination of factors including an expansion in the types of patients considered likely to benefit from TKA, an aging population, and an increasing prevalence of certain conditions that predispose patients to osteoarthritis, most notably obesity.”

“The growth in TKA should prompt consideration of whether too many (or too few) of these procedures are being performed both in aggregate and among key patient subgroups defined by race, sex, or age.”

(JAMA. 2012;308[12]:1227-1236. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work is funded in-part by grants from the NHLBI and from the NIA. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, September 25 at this link.

Editorial: Increasing Use of Total Knee Replacement and Revision Surgery

James Slover, M.D., M.S., and Joseph D. Zuckerman, M.D., of the Hospital for Joint Diseases of New York University Langone Medical Center, New York, comment on the findings of this study in an accompanying editorial.

“The report by Cram et al characterizes some important epidemiologic aspects of primary and revision knee replacement that have occurred over the past 20 years, including the evolution of increased volume and changes in care patterns, complication, and readmission rates. In an effort to control costs and improve quality of care, the findings provide important information concerning patient demographics associated with primary and revision total knee replacements and complications. In the currently challenging and dynamic health care environment, critical evaluation and systematic data collection about total knee replacements will be needed to optimize outcomes and ensure access to these life-improving procedures.”

(JAMA. 2012;308[12]:1266-1268. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Zuckerman reported earning royalties for designing a shoulder arthroplasty system. Dr. Slover reported no financial conflict.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Higher Amounts of Aerobic Exercise By Overweight Children Reduces Risk of Diabetes

Child obesity and overweight are epidemic among U.S. children, with a third of elementary school-aged children being overweight or obese. Childhood obesity is associated with a number of adverse conditions formerly thought to occur only in adults, including type 2 diabetes, according to background information in the article. “Previous studies in children have shown reduction in metabolic risk factors through exercise, but dose-response information needed to formulate evidence-based public health recommendations for children is not available.”

Catherine L. Davis, Ph.D., of the Medical College of Georgia, Augusta, and colleagues conducted a study to test the effect of different amounts of aerobic training on insulin resistance, fatness, visceral (abdominal) fat, and fitness in overweight, sedentary children. The randomized controlled trial was conducted from 2003 through 2007 and included 222 overweight or obese sedentary children (average age, 9.4 years; 42 percent male; 58 percent black). Children were randomly assigned to low-dose (20 min/day; n = 71) or high-dose (40 min/day; n = 73) aerobic training (5 day/week; average duration, 13 weeks) or a control condition (usual physical activity; n = 78). The pre-specified primary outcomes were post-intervention type 2 diabetes risk, as assessed by certain measures of insulin, aerobic fitness, percent body fat, and visceral fat.

The researchers found that reductions in the measure of insulin were greater in the high-dose aerobic training group and the low-dose group than the control group. Dose-response trends were also observed for body fat and visceral fat in the high- and low-dose vs. control groups. Effects in the high- and low-dose groups vs. control were similar for fitness.

“In conclusion, in this randomized controlled trial, 13 weeks of 20-or 40-min/day aerobic training resulted in improvement in diabetes risk as estimated by insulin resistance, fitness, and general and visceral adiposity [body fat] in sedentary overweight or obese children regardless of race or sex, with a dose-response gradient for insulin resistance and adiposity.”

(JAMA. 2012;308[11]:1103-1112. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health and a grant from the Salvador de Madariaga Program of the Spanish Ministry of Education and Science. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. This JAMA theme issue is being published the same week as the Obesity Society’s Annual Scientific Meeting.

Media Advisory: To contact Catherine L. Davis, Ph.D., call Toni Baker at 706-721-4421 or email tbaker@georgiahealth.edu.

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Study Examines Long-Term Health Care Use Following Bariatric Surgery

“Bariatric surgery reduces weight and improves diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea. Long-term outcomes for surgically induced weight loss from the Swedish Obese Subjects study have demonstrated sustained weight loss, reduced incidence of diabetes, cardiovascular events, and cancer, as well as improved 10- to 15-year survival. Although there are many benefits from bariatric surgery, it is not known whether these translate to reduced long-term health care use,” according to background information in the article.

Martin Neovius, Ph.D., of the Karolinska Institute, Sweden, and colleagues from the Sahlgrenska Academy assessed the amount of health care obese patients used over 20 years after undergoing bariatric surgery, compared with obese patients who were conventionally treated. The Swedish Obese Subjects study is an ongoing, prospective, controlled intervention study conducted in the Swedish health care system that included 2,010 adults who underwent bariatric surgery and 2,037 contemporaneously matched controls recruited between 1987 and 2001. Inclusion criteria were age 37 years to 60 years and body mass index of 34 or higher in men and 38 or higher in women. Of the surgery patients, 13 percent underwent gastric bypass, 19 percent gastric banding, and 68 percent vertical-banded gastroplasty. Controls received conventional obesity treatment.

The relative weight changes at 20 years for those in the surgery group was a loss of 18 percent vs. a loss of 1 percent among those in the control group; the surgery group had a 44.1 lbs. greater weight loss than non-surgery controls.

The researchers found that “despite considerably greater and sustained weight loss than conventionally treated controls, surgically treated patients used more inpatient and nonprimary outpatient care during the 6-year period after the index date but not thereafter. Cost savings in the surgery group were seen for medications that treat diabetes and cardiovascular disease between year 7 and 20, resulting in lower overall drug costs during that period.”

(JAMA. 2012;308[11]:1132-1141. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Media Advisory: To contact Martin Neovius, Ph.D., email Martin.Neovius@ki.se.

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 Bariatric Surgery Does Not Result in Statistically Greater Reduction in Sleep Apnea Compared to Conventional Weight Loss Program

“Obesity is a major risk factor for obstructive sleep apnea (OSA). The estimated prevalence of OSA in obese adults varies from 42 percent to 48 percent in men and 8 percent to 38 percent in women,” according to background information in the article. Individuals with OSA are at greater risk of stroke, cardiac disease, cognitive dysfunction, and impaired quality of life. Observational studies of major weight loss following bariatric surgery have suggested substantial remission of OSA symptoms. There have not been any randomized controlled trials comparing medically supervised weight loss with bariatric surgery as a treatment for OSA.

John B. Dixon, M.B.B.S., Ph.D., F.R.A.C.G.P., of Baker IDI Heart and Diabetes Institute and the Obesity Research Unit, Monash University, Melbourne, Australia, and colleagues conducted a randomized controlled trial comparing laparoscopic adjustable gastric banding (LAGB) with conventional weight loss therapy for the management of moderate to severe OSA in 60 obese patients (body mass index: >35 and <55). The patients had recently diagnosed (<6 months) OSA and an apnea-hypopnea index (AHI) of 20 events/hour or more. These patients had been prescribed continuous positive airway pressure (CPAP) therapy to manage OSA and were identified via accredited community sleep clinics. The trial was conducted between September 2006 and March 2009. Patients were randomized to a conventional weight loss program that included regular consultations with a dietitian and physician, and the use of very low-calorie diets as necessary (n = 30) or to laparoscopic adjustable gastric banding; n = 30). The primary outcome measure for the study was baseline to 2-year change in AHI on diagnostic polysomnography.

Patients lost an average of 11.2 lbs. in the conventional weight loss program compared with 61.3 lbs. in the bariatric surgery group. The researchers found that both groups had a significant decrease in total AHI between baseline and 2 years, with a decrease of 25.5 events/hour, from 65.0 events/hour to 39.5 events/hour in the surgical group; and a decrease of 14.0 events/hour, from 57.2 events/ hour to 43.2 events/hour in the conventional group. The between-group difference was -11.5 events/hour or percentage change in AHI of -17.9 percent. CPAP adherence did not differ between the groups.

“Comparing surgical and conventional weight loss therapy for the management of OSA demonstrated greater weight loss in the surgically treated group, however, this did not translate into significantly greater improvements in OSA,” the authors write. “While there is a clear overall response to weight loss, the individual effects are variable, incomplete, and appear to be related to modest weight loss. This study suggests caution be used in counseling patients about the expected benefits of weight loss for OSA, and that patients losing weight be assessed appropriately before ceasing effective therapy.”

(JAMA. 2012;308[11]:1142-1149. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Media Advisory: To contact John B. Dixon, M.B.B.S., Ph.D., F.R.A.C.G.P., email john.dixon@bakeridi.edu.au.

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 Viewpoints in This Week’s JAMA

 The Next Generation of Obesity Research – No Time to Waste

Griffin P. Rodgers, M.D., and Francis S. Collins, M.D., Ph.D., of the National Institutes of Health, Bethesda, Md., write that compared to previous health crises the U.S. has faced, “obesity may pose the most significant challenge yet because it involves changing approaches to 2 fundamental aspects of daily life: food consumption and physical activity. To have any chance of release from obesity’s ever-tightening grip, the nation will require broad-based efforts in every corner of society; homes, schools, community organizations, all levels of government, urban design, transportation, agriculture, the food industry, the media, medical practice, and, without question, biomedical research.”

The authors suggest that to help address this issue, more rigorous data are needed on what approaches can help achieve and maintain healthy body weights over the long term. There is also a need for more basic research aimed at expanding understanding of the molecular basis of obesity, and research focused on understanding the environmental risk factors for obesity. Behavioral and other kinds of research should also further explore strategies involving innovative technologies.

“While there are many key differences between the obesity epidemic and the health threats posed by tobacco use, infant mortality, and HIV/AIDS, the nation’s clinicians, researchers, policy makers, food producers, business owners, educators, community leaders, and citizens should consider what it took to make significant progress against those formidable foes. Can the United States again rise to the challenge and change its attitudes, policies, behaviors, and environments in some fundamental ways? The health of the next generation depends on the answer.”

(JAMA. 2012;308[11]:1095-1096. Available pre-embargo to the media at http://media.jamanetwork.com)

FDA Approval of Obesity Drugs – A Difference in Risk-Benefit Perceptions

Elaine H. Morrato, Dr.P.H., M.P.H., of the University of Colorado Denver, Aurora, and David B. Allison, Ph.D., of the University of Alabama at Birmingham, write that in the last decade, 3 obesity drugs were removed from the U.S. market, and until last month, only 1 new obesity drug has been approved since 1999. “Some observers question whether new obesity drugs are being held to a higher regulatory standard.” In this Viewpoint, the authors offer suggestions on how to improve the transparency of risk-benefit deliberations for obesity drugs, as well as other drugs that are used broadly in the population and that require Advisory Committee review.

“Reviewing drugs is an inherently challenging task. Consideration of the cognitive factors influencing risk-benefit deliberations may be a useful step toward making the review of obesity drugs more transparent to physicians and patients. The tendency to think dichotomously inherently makes balancing the potential risks against the potential benefits of drugs difficult, as does the inherent difficulty in adopting alternative perspectives (e.g., patient vs. society vs. regulator). Explicit discussions of this dichotomy and reminders to advisory board members of their charge may help to overcome these challenges for the good of prospective patients.”

(JAMA. 2012;308[11]:1097-1098. Available pre-embargo to the media at http://media.jamanetwork.com)

Cardiovascular Risk Assessment in the Development of New Drugs for Obesity

William R. Hiatt, M.D., of the University of Colorado School of Medicine, Aurora, and colleagues write that the U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research, convened a meeting of the Division of Metabolism and Endocrinology Products in March 2012 to consider cardiovascular safety requirements for approval of new drugs to treat obesity. Because obesity is associated with excess cardiovascular risk and weight loss treatments could potentially mitigate that risk, it is important to assess the effect of these drugs on cardiovascular morbidity and mortality.” The authors examine the issue of evaluating cardiovascular risk for obesity drugs.

“The deliberations of the U.S. FDA Endocrinologic and Metabolic Drugs Advisory Committee provide insight into the challenges and recommendations for developing new antiobesity drugs. Key considerations include demonstrating that any degree of drug-induced weight loss is associated with short-term and longer-term clinical benefits. Assessment of cardiovascular safety has emerged as a major consideration for all new antiobesity drugs under current review. If there is a change in the regulatory approval process, it is likely the FDA will issue a revised guidance document for development of weight-loss products addressing these issues. At present, use of any new drugs that enter the market without long-term safety data should be limited to patients similar to those studied in the pivotal trials.”

(JAMA. 2012;308[11]:1099-1100. Available pre-embargo to the media at http://media.jamanetwork.com)

 Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact Thomas A. Farley, M.D., M.P.H., call Jean Weinberg at 347-396-4177 or email jweinberg@health.nyc.gov.

NEW YORK – Addressing the obesity epidemic by preventing excess calorie consumption with government regulation of portion sizes is justifiable and could be an effective measure to help prevent obesity-related health problems and deaths, according to a Viewpoint in the September 19 issue of JAMA, and theme issue on obesity.

Thomas A. Farley, M.D., M.P.H., Commissioner of the New York City Department of Health and Mental Hygiene, presented the article at a JAMA media briefing.

“Americans consume many more calories than needed, and the excess is leading to diabetes, cardiovascular disease, and premature mortality. Since the 1970s, caloric intake has increased by some 200 to 600 calories per person per day. Although it is unclear how important changes in physical activity are to the surge in obesity prevalence, it is quite clear that this increase in calorie consumption is the major cause of the obesity epidemic—an epidemic that each year is responsible for the deaths of more than 100,000 Americans and accounts for nearly $150 billion in health care costs,” writes Dr. Farley.

Many foods contribute to excess calorie intake, Dr. Farley adds, but sugary drinks have drawn particular blame because of the near-tripling of consumption since the 1970s and their association in epidemiologic studies with obesity, weight gain, diabetes, and markers of cardiovascular disease. Also, the size of sugary drinks sold has increased substantially from a standard 6.5- or 8-ounce size in the 1960s to 20, 32, and even 64 ounces today. “The increase in portion sizes of these beverages is important because studies consistently show that when people are offered larger portions they simply consume more without recognizing it and without compensating for the increased consumption by decreasing intake later.”

Dr. Farley writes that the food industry is effective at marketing foods with a high-profit margin. “How should government address the health problems caused by this successful marketing of food? To do nothing is to invite even higher rates of obesity, diabetes, and related mortality.”

He suggests one option is to encourage food companies to voluntarily alter their products or marketing to reduce health risks. “Food companies understand how customers respond to their products and marketing better than anyone and could make many changes that would promote health. Food companies have indeed been responding to the obesity crisis by marketing products that have lower calorie contents by substitution (as with ‘diet’ beverages) and more recently by offering smaller portions. However, as publicly traded companies responsive to the interests of their shareholders, food companies cannot make decisions that will lower profits, and larger portion sizes are more profitable because most costs of delivering food items to consumers are fixed.”

“The balanced and most effective approach is for governments to regulate food products that harm the most people, simultaneously encourage food companies to voluntarily produce and market healthful products, and then provide information to consumers in ways that facilitate their choosing healthful products.”

Dr. Farley cites a number of initiatives taken by New York City to improve public health, including requiring restaurants to eliminate artificial trans fat, working with food companies to voluntarily lower sodium levels in packaged/processed foods, and providing information to consumers by requiring that chain restaurants  post calorie counts on their menus and menu boards. These actions followed similar steps to address smoking, which have led to a 35 percent reduction in smoking rates in the city in the past 10 years.

Dr. Farley describes steps taken by the city to address what many believe is the greatest single contributor to the obesity epidemic—sugary drinks. Among the initiatives, New York City supported a 1-cent-per-ounce excise tax on sugary drinks; the city also supported a change in policy on the Supplemental Nutrition Assistance Program that would have prohibited the use of program benefits to purchase sugary drinks; and the city’s Health Department proposed a cap on the portion size of sugary drinks served at restaurants. “… the portion-size studies strongly suggest that, with a smaller default portion size, most consumers will consume fewer calories. This change will not by itself reverse the obesity epidemic, but it can have a substantial effect on it.”

“Although the idea of government action to prevent obesity by regulating portion size is new, this action is easily justifiable, is manageable by the dynamic food industry, and will be effective in preventing needless deaths,” Dr. Farley concludes.

(JAMA. 2012;308[11]:1093-1094. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact James A. de Lemos, M.D., call Lisa Warshaw at 214-648-9349 or email lisa.warshaw@utsouthwestern.edu.

NEW YORK – Obese adults with excess visceral fat (fat located inside the abdominal cavity, around the body’s internal organs) and biomarkers of insulin resistance had an associated increased risk for the development of type 2 diabetes mellitus, while obese individuals with higher amounts of total body fat and subcutaneous fat (underneath the skin) did not have this increased risk, according to a study in the September 19 issue of JAMA, and theme issue on obesity.

James A. de Lemos, M.D., of the University of Texas Southwestern Medical Center, Dallas, presented the findings of the study at a JAMA media briefing.

“A marked increase in the prevalence of overweight and obesity has contributed to a doubling in type 2 diabetes mellitus incidence over the past three decades,” according to background information in the article. “Prediabetes, an intermediate hyperglycemia phenotype and risk factor for diabetes, is also associated with obesity and carries an excess risk for cardiovascular disease (CVD) and death. Although increased body mass index (BMI) is associated with diabetes at the population level, it does not adequately discriminate diabetes risk among obese individuals. Indeed, many obese persons appear resistant to the development of metabolic disease. Because the metabolic disease risks associated with obesity are heterogeneous [dissimilar], there remains an unmet clinical need for tools that differentiate obese persons who will ultimately develop prediabetes and diabetes from those who will remain metabolically healthy.”

Dr. de Lemos and colleagues examined the associations of adipose (body fat) tissue distribution, lipids, and biomarkers of insulin resistance and inflammation with the risk of prediabetes and diabetes in obese adults. The study included 732 obese participants (body mass index 30 or greater) ages 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study.

The researchers measured body composition by dual energy x-ray absorptiometry (low dose x-ray to determine amounts and distribution of body fat) and magnetic resonance imaging (MRI); circulating adipokines (proteins secreted by fat tissue) and biomarkers of insulin resistance, dyslipidemia (abnormal cholesterol levels), and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI.

Over a median (midpoint) follow-up of 7 years, 84 participants (11.5 percent) developed diabetes. In multivariable analysis, higher measures of visceral fat mass at the beginning of the study, fructosamine level (a measurement used to estimate  the average plasma glucose concentration over several weeks), fasting glucose level, family history of diabetes, systolic blood pressure, and weight gain over the follow-up period were independently associated with the development of diabetes.

The composite outcome of prediabetes or diabetes occurred in 39.1 percent of 512 participants with normal baseline glucose values, and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; non-white race; family history of diabetes; and weight gain over follow-up, but not with measurements of general adiposity.

Diabetes incidence increased significantly among individuals with higher categories of visceral fat mass, but no association was seen for abdominal subcutaneous fat, total body fat or body mass index.

“These findings suggest that clinically measurable markers of adipose tissue distribution and insulin resistance may be useful in prediabetes and diabetes risk discrimination among obese individuals and support the notion of obesity as a heterogeneous disorder with distinct adiposity subphenotypes,” the authors write.

“Further research is needed to determine whether assessment of adipose tissue distribution and function using imaging tools, circulating biomarkers, or both can improve clinical risk prediction in obese individuals.”

(JAMA. 2012;308[11]:1150-1159. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. This JAMA theme issue is being published the same week as the Obesity Society’s Annual Scientific Meeting.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact Ted D. Adams, Ph.D., M.P.H., call Jennifer Barrett at 801-408-2182 or email jennifer.barrett@imail.org. To contact editorial author Anita P. Courcoulas, M.D., M.P.H., call Amy Dugas Rose at 412-586-9776 or email dugasak@upmc.edu.

NEW YORK – Severely obese patients who had Roux-en-Y gastric bypass surgery had significant weight loss that was sustained for an average of 6 years after the surgery and also experienced frequent remission and lower incidence of diabetes, hypertension, and abnormal cholesterol levels, compared to participants who did not have the surgery, according to a study in the September 19 issue of JAMA, and theme issue on obesity.

Ted D. Adams, Ph.D., M.P.H., of the University of Utah School of Medicine and Intermountain Healthcare, Salt Lake City, presented the findings of the study at a JAMA media briefing.

“The prevalence of extreme obesity in the United States is increasing at a rate greater than moderate obesity. Unfortunately, lifestyle therapy is generally insufficient as a weight management intervention for patients who are extremely obese. To date, effective long-term weight loss through pharmacological therapy has been marginal, leaving bariatric surgery as the only medical intervention providing substantial, long-term weight loss for most patients who are severely obese. For this high-risk population, however, the number of studies reporting long-term weight loss following bariatric surgery are limited and generally have incomplete follow-up,” according to background information in the article.

Dr. Adams and colleagues conducted a study to examine the association of Roux-en-Y gastric bypass (RYGB) surgery with weight loss, diabetes mellitus, and other health risks 6 years after surgery. The study included 1,156 severely obese (body mass index [BMI] 35 or greater) participants, ages 18 to 72 years (82 percent women; average BMI, 46) who sought and received RYGB surgery (n = 418), sought but did not have surgery (n = 417; control group 1), or who were randomly selected from a population-based sample not seeking weight loss surgery (n = 321; control group 2).

At 6 years, 92.6 percent (387/418) of the surgical group had follow-up data. Average unadjusted weight loss in the surgical group was 27.7 percent from the beginning of the study to year 6. Weight gain from baseline to year 6 was 0.2 percent in control group 1 and 0 percent in control group 2. “At 2 years, 99 percent of surgical patients had maintained more than 10 percent weight loss from baseline and 94 percent had maintained more than 20 percent weight loss. At 6 years, 96 percent of surgical patients had maintained more than 10 percent weight loss from baseline and 76 percent had maintained more than 20 percent weight loss,” the authors write.

The 6-year RYGB surgery group diabetes remission rates were significantly higher than the 2 control groups (62 percent for RYGB surgery group; vs. 8 percent for control group 1; and 6 percent for control group 2). At the same time, diabetes incidence in the RYGB surgery group was significantly lower than in the 2 control groups (2 percent vs. 17 percent and 15 percent; respectively). Remission rates of hypertension and low HDL-C levels at year 6 remained significantly improved in the RYGB surgical group compared with the 2 control groups, with similar improvements observed with remission rates for high LDL-C levels and high triglyceride levels. The numbers of participants with bariatric surgery-related hospitalizations were 33 (7.9 percent), 13 (3.9 percent), and 6 (2.0 percent) for the RYGB surgery group and 2 control groups, respectively.

The authors write that metabolic and cardiovascular risk profiles during the 6 years of follow-up remained significantly improved after RYGB surgery. “In contrast, cardiovascular and metabolic status of severely obese control participants generally worsened during the 6-year period.”

“These findings are important considering the rapid increase in total numbers of bariatric surgical operations performed in the United States and worldwide, and may have significant ramifications for the projected 31 million U.S. individuals meeting criteria for bariatric surgery.”

(JAMA. 2012;308[11]:1122-1131. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the National Institutes of Health/The National Institute of Diabetes and Digestive and Kidney Diseases and a Public Health Service research grant from the National Center for Research Resources. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc. This JAMA theme issue is being published the same week as the Obesity Society’s Annual Scientific Meeting.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 10 a.m. ET Tuesday, September 18 at this link.

Editorial: Progress in Filling the Gaps in Bariatric Surgery

In an accompanying editorial, Anita P. Courcoulas, M.D., M.P.H., of the University of Pittsburgh Medical Center, writes that an “important aspect of these findings is that despite the attenuation [lessening] of weight loss between 2 and 6 years in the RYGB group, the control of comorbid conditions remained very good.”

“These findings are important because they show in a RYGB cohort and control group with nearly complete follow-up at 6 years that weight loss and associated health benefits following RYGB are durable. The mortality rates in this study were too small to assess statistically, but serve as a reminder of an uncommon but important outcome needing objective monitoring.”

(JAMA. 2012;308[11]:1160-1161. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, financial disclosures, funding and support, etc.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact Leonardo Trasande, M.D., M.P.P., call Jessica Guenzel at 212-404-3591 or email Jessica.Guenzel@nyumc.org.

NEW YORK – In a nationally representative sample of nearly 3,000 children and adolescents, those who had higher concentrations of urinary bisphenol A (BPA), a manufactured chemical found in consumer products, had significantly increased odds of being obese, according to a study in the September 19 issue of JAMA, and theme issue on obesity.

Leonardo Trasande, M.D., M.P.P., of the NYU School of Medicine, New York City, presented the findings of the study at a JAMA media briefing.

“In the U.S. population, exposure [to BPA] is nearly ubiquitous, with 92.6 percent of persons 6 years or older identified in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) as having detectable BPA levels in their urine. A comprehensive, cross-sectional study of dust, indoor and outdoor air, and solid and liquid food in preschool-aged children suggested that dietary sources constitute 99 percent of BPA exposure,” according to background information in the article. “In experimental studies, BPA exposure has been shown to disrupt multiple metabolic mechanisms, suggesting that it may increase body mass in environmentally relevant doses and therefore contribute to obesity in humans.” BPA exposure is plausibly linked to childhood obesity, but evidence is lacking.

Dr. Trasande and colleagues conducted a study to examine association between urinary BPA concentrations and body mass in children. The study consisted of a cross-sectional analysis of a nationally representative subsample of 2,838 participants, ages 6 through 19 years, randomly selected for measurement of urinary BPA concentration in the 2003-2008 National Health and Nutrition Examination Surveys. Body mass index (BMI), converted to sex- and age-standardized z scores (indicates how many units [of the standard deviation] a child’s BMI is above or below the average BMI value for their age group and sex) was used to classify participants as overweight (BMI 85th percentile or greater for age/sex) or obese (BMI 95th percentile or greater). The median (midpoint) urinary BPA concentration for participants in the study was 2.8 ng/mL. The prevalence of obesity was 17.8 percent (n = 590), and overweight 34.1 percent (n = 1,047). The BPA concentrations of the participants were divided into quartiles (four groups). Controlling for race/ethnicity, age, caregiver education, poverty to income ratio, sex, serum cotinine level, caloric intake, television watching, and urinary creatinine level, children in the lowest urinary BPA quartile had a lower estimated prevalence of obesity (10.3 percent) than those in quartiles 2 (20.1  percent), 3 (19.0 percent), and 4 (22.3 percent). Compared with the first quartile, participants in the third quartile had approximately twice the odds for obesity. Participants in the fourth quartile had a 2.6 higher odds of obesity.

Further analyses showed this association to be statistically significant in only 1 racial subpopulation, white children and adolescents. The researchers also found that obesity was not associated with exposure to other environmental phenols commonly used in other consumer products, such as sunscreens and soaps.

“To our knowledge, this is the first report of an association of an environmental chemical exposure with childhood obesity in a nationally representative sample,” the authors write.

The researchers note that advocates and policy makers have long been concerned about BPA exposure. “We note the recent FDA ban of BPA in baby bottles and sippy cups, yet our findings raise questions about exposure to BPA in consumer products used by older children. Last year, the FDA declined to ban BPA in aluminum cans and other food packaging, announcing ‘reasonable steps to reduce human exposure to BPA in the human food supply’ and noting that it will continue to consider evidence on the safety of the chemical. Carefully conducted longitudinal studies that assess the associations identified here will yield evidence many years in the future.”

(JAMA. 2012;308[11]:1113-1121. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Study Analyzes Changes in Pharmaceutical Advertising Following Shift to OTC Status

“The U.S. Food and Drug Administration (FDA) regulates prescription drug advertising, including requirements to provide consumers with a ‘fair balance’ of risks and benefits. When prescription drugs switch to over-the-counter (OTC) status, regulatory oversight of their advertising shifts to the Federal Trade Commission (FTC). Unlike the FDA, the FTC holds drug advertisements to the same standards as any consumer product: it applies a ‘reasonable consumer’ standard of truthfulness and nondeception that does not require any balancing of potential benefits and harms. Such a shift may be associated with changes in content,” writes Jeremy A. Greene, M.D., Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues.

As reported in a Research Letter, the authors analyzed all print and broadcast advertisements from 4 commonly used prescription drugs that were the subject of extensive direct-to-consumer advertising (DTCA) promotion before and after OTC shift: loratidine (OTC in 2002), omeprazole (in 2004), orlistat (in 2007), and cetirizine (in 2008). Television and print materials spanning 24 months before and 6 months following OTC shift for each drug were obtained from an advertising database, and ads were stratified by whether they appeared in print or television, and coded for descriptive characteristics, presentation of health benefits, and potential health harms.

The researchers found that after the OTC switch, 62 of 64 (97 percent) advertisements described benefits of medications compared with 57 of 69 (83 percent) during the prescription only period. “The difference was not statistically significant for individual drugs. Differences existed in the presentation of potential harms during the prescription-only period in 48 of 69 advertisements (70 percent) vs. 7 of 64 (11 percent) after OTC shift. With the exception of print advertisements for orlistat, no post-switch advertisements mentioned contraindications or adverse effects. Print and broadcast advertisements after OTC switch were less likely to mention drugs’ generic names (33 of 64 [52 percent] vs. 65 of 69 [94 percent]).”

(JAMA. 2012;308[10]:973-975. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

The Attending Physician on the Wards – Finding a New Homeostasis

Robert M. Wachter, M.D., of the University of California, San Francisco, and Abraham Verghese, M.D., M.A.C.P., of Stanford University, Stanford, Calif., examine the changes that have taken place in recent years regarding attending physicians, including the reasons for the marked shift in demographics (such as from older to younger attendings), consider its effects on education and clinical care, and suggest interventions that may help improve the experience of trainees as well as attendings.

“Although some challenges will be more easily addressed by junior attendings and others by senior ones, the goals are the same. All attendings will need encouragement and wisdom to take a step back, keeping a measured distance that allows house staff to achieve and demonstrate competency while still ensuring patient safety. It is time that programs, trainees, and attendings take vigorous action to balance all these competing imperatives and establish a ‘new normal.’”

(JAMA. 2012;308[10]:977-978. Available pre-embargo to the media at http://media.jamanetwork.com)

Engaging Physicians and Leveraging Professionalism – A Key to Success for Quality Measurement and Improvement

Patrick H. Conway, M.D., M.Sc., of the Centers for Medicare & Medicaid Services, Baltimore, and Cincinnati Children’s Hospital Medical Center, and Christine K. Cassel, M.D., M.Sc., of the American Board of Internal Medicine, Philadelphia, discuss the topic of quality measurement and improvement, including the implementation of Maintenance of Certification, which includes assessment of physician performance. Also, the authors examine initiatives by the Centers for Medicare & Medicaid Services on this topic.

(JAMA. 2012;308[10]:979-980. Available pre-embargo to the media at http://media.jamanetwork.com)

Surgical vs. Lifestyle Treatment for Type 2 Diabetes

David S. Ludwig, M.D., Ph.D., of Boston Children’s Hospital, and colleagues write that “recent clinical trials have reported that substantially more weight loss and greater likelihood of diabetes remission occur following bariatric surgery compared with medical therapy, leading to calls for earlier consideration of surgery in the treatment of this obesity-related metabolic disease. Although these studies demonstrate the lack of efficacy of conventional practices, they do not prove the inherent superiority of surgery to lifestyle change.”

In this Viewpoint, the authors consider the limitations of published research and highlight the need for clinical trials with improved design.

“Before bariatric surgery becomes a mainstay for obesity-related complications, additional research is needed to compare the efficacy and safety of these procedures with that of truly intensive lifestyle intervention, not just standard practice. Design issues warranting consideration include the need for standardization of treatment, statistical methods (e.g., superiority vs. noninferiority trial), and generalizability. Because drug and device manufacturers would not profit from, and therefore have little incentive to sponsor, lifestyle intervention, the federal government should consider funding this research as a high priority.”

(JAMA. 2012;308[10]:981-982. Available pre-embargo to the media at http://media.jamanetwork.com)

Changing Eating Habits for the Medical Profession

Lenard I. Lesser, M.D., M.S.H.S., of the Palo Alto Medical Foundation Research Institute, Palo Alto, Calif., and colleagues write that health professionals spend a great deal of time at meetings. “Grand rounds, noon seminars, research meetings, and medical conferences are part of the life of a health professional. At many of these activities, food is available. Although some members of the health professional community have called for changes to the food environment in the community in which they live, they have paid less attention to the quality of food served at hospitals, physician offices, and at conferences.”

The authors examine steps that the medical profession can take to improve eating habits.

“The medical profession was influential in reducing smoking in the United States; it has the capacity to encourage food-system change within its own institutions. This would likely reduce caloric consumption of health professionals, promote the health of physicians, and could also cause a ripple effect in local food economies.”

(JAMA. 2012;308[10]:983-984. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact Carrie H. Colla, Ph.D., call Annmarie Christensen at 603-653-0897 or email annmarie.christensen@dartmouth.edu. To contact editorial author Donald M. Berwick, M.D., M.P.P., email donberwick1@gmail.com.

CHICAGO – In an analysis of the cost-savings achieved by an earlier pilot program, the Medicare Physician Group Practice Demonstration (PGPD), researchers found modest estimates of overall savings associated with the PGPD, but larger savings among the dually eligible patients (Medicare and Medicaid), with savings achieved in large part through reductions in hospitalizations, according to a study in the September 12 issue of JAMA.

“To improve care and slow cost growth, payers are increasingly turning to new payment models, including accountable care organizations (ACOs). The Centers for Medicare & Medicaid Services (CMS) has launched 3 ACO programs—Pioneer, the Shared Savings Program, and the Advance Payment Model—which differ slightly in their details but share a common approach: participating organizations can share in savings if they meet quality and cost targets for their assigned beneficiaries. Accountable care organizations were included in the Affordable Care Act in part because simulations suggested that CMS could achieve savings from these models, and an earlier program, the Physician Group Practice Demonstration, appeared to be effective,” according to background information in the article.

In the PGPD program, participating physician groups were eligible for up to 80 percent of any savings they generated if they were also able to demonstrate improvement on 32 quality measures, including the adequacy of preventive care and the effectiveness of chronic disease management. “Although evidence indicates the PGPD improved quality, uncertainty remains about its effect on costs,” the authors write.

Carrie H. Colla, Ph.D., of the Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth, Lebanon, N.H., and colleagues conducted a study to estimate the cost savings achieved by the PGPD program for all beneficiaries and for both dually and nondually eligible beneficiaries. The analyses compared pre-intervention (2001-2004) and post-intervention (2005-2009) trends in spending of PGPD participants to local control groups. The study included 10 physician groups from across the United States. The intervention group was composed of fee-for-service Medicare beneficiaries (n = 990,177) receiving care primarily from the physicians in the participating medical groups. Controls were Medicare beneficiaries (n = 7,514,453) from the same regions who received care largely from non-PGPD physicians. Overall, 15 percent of beneficiaries were dually eligible for Medicare and Medicaid. The primary outcome measure for the study was annual spending per Medicare fee-for-service beneficiary.

For all enrollees, the reduction in growth of spending for nondually eligible beneficiaries was modest. After adjustment, annual savings estimates per beneficiary were modest ($114), with this result reflecting the average of significant annual savings in the dually eligible beneficiaries ($532) and nonsignificant savings in the nondually eligible beneficiaries ($59, $166 in savings to $47 in additional spending).

The adjusted average spending reductions were concentrated in acute care (overall, $118; dually eligible: $381; nondually eligible: $85). Further analysis revealed that in sites where savings occurred for acute care, hospitalization rates declined during the PGPD.

The PGPD was associated with lower medical 30-day readmissions on average across the 10 sites and lower readmissions for both medical and surgical admissions in the dually eligible beneficiaries. There was significant variation in savings across practice groups, ranging from an overall mean per-capita annual saving of $866 to an increase in expenditures of $749.

“The variation both in levels and changes in risk-adjusted spending across the participating organizations was remarkable. We know little about why some succeeded and others failed to achieve savings. One hypothesis is that organizations beginning with higher spending levels have greater opportunities to achieve savings,” the authors write. “Other factors may have contributed to achieving higher levels of performance in some sites, such as governance models; internal leadership; physician engagement strategies; the degree of coherence of electronic health records and other health information technological tools; and the specific approaches adopted for chronic disease management, care transitions, and quality improvement.”

“Our results suggest that the ACO reforms included in the Affordable Care Act, such as the Pioneer and the Medicare Shared Savings Programs, have at least the potential to slow spending growth, particularly for costly patients. The remarkable degree of heterogeneity across participating sites underscores the importance of timely evaluation of current payment reforms and a better understanding of the institutional factors that lead to either success or failure in effecting changes in health care practices.”

(JAMA. 2012;308[10]:1015-1023. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This research was funded by a grant from the National Institute on Aging, the Dartmouth Atlas Project (supported by a consortium led by the Robert Wood Johnson Foundation), and the Commonwealth Fund.  All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: ACOs—Promise, Not Panacea

In an accompanying editorial, Donald M. Berwick, M.D., M.P.P., former president and CEO of the Institute for Healthcare Improvement and former Administrator of the Centers for Medicare & Medicaid Services, examines the question of what this new analysis adds to predictions about the promise of ACOs.

“First, the results for dually eligible beneficiaries are important and encouraging. Most of the 9.2 million people in that Medicare subgroup receive poor, uncoordinated care in the status quo, and they account for over $300 billion in annual costs and 40 percent of state Medicaid expenditures. Improvements of cost and quality for them can have big payoffs. Second, the Dartmouth group documented a small overall savings for the entire beneficiary population and, were this to be multiplied over the whole of Medicare, the total would be about $5 billion per year, that is, about 1 percent of the budget. Third, the substantial variation of results among PGPD sites offers hope for continual learning about best practices, and therefore, maybe, better results in more places over time. Fourth, the evidence of what the authors gently call ‘coding biases’ in PGPD sites serves notice once again that surveillance by CMS and objective evaluators is necessary and prudent. Neither patients nor the nation are well served when administrative manipulations masquerade as changes in care. What is needed is better care, not better coding.”

(JAMA. 2012;308[10]:1038-1039. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact corresponding author Joachim Klode, M.D., email joachim.klode@uk-essen.de.

CHICAGO – Preoperative 3-dimensional visualization of sentinel lymph nodes (SLNs) with a technique known as single-photon emission computed tomography/computed tomography was associated with a higher rate of detection of positive SLNs and a higher rate of disease-free survival among patients with melanoma, according to a study in the September 12 issue of JAMA.

“Melanoma has become an increasing interdisciplinary public health challenge worldwide. According to the World Health Organization, the incidence of melanoma is increasing faster than any other cancer in the world. Melanoma is the third most common cancer in Australia and the fifth most common cancer in the United States. The American Cancer Society estimated that approximately 70,230 new melanomas were diagnosed in the United States during 2011, resulting in approximately 8,790 deaths,” according to background information in the article. “Because melanoma, depending on tumor depth, metastasizes early into regional lymph nodes, sentinel lymph node excision (SLNE) is probably the most important diagnostic and potentially therapeutic procedure for patients with melanoma. The histological status of the sentinel lymph node is the most relevant prognostic factor for overall survival in patients with melanoma, independent of primary tumor thickness.” The authors add that the recently introduced hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) imaging technique could help overcome the high false-negative rate of SLNE by providing additional anatomical information to the surgeon.

Ingo Stoffels, M.D., of the University of Essen-Duisburg, Essen, Germany, and colleagues conducted a study to compare the association between SLNE with vs. without preoperative SPECT/CT imaging and metastatic node detection and disease-free survival in patients with cutaneous melanoma. The study included use of a melanoma patient database to identify a group of 464 patients eligible for SLNE between March 2003 and April 2011. A total of 403 patients with clinically negative lymph nodes, who underwent SLNE with or without preoperative SPECT/CT, qualified for subsequent analysis. Between March 2003 and October 2008, 254 patients with melanoma underwent SLNE without preoperative SPECT/CT. Between November 2008 and April 2011, all sentinel node scintigraphies (type of diagnostic imaging tests) were performed as SPECT/CT in 149 patients. Using SPECT/CT allowed SLNE in the head and neck area more frequently (2.0 percent for standard vs. 23.5 percent for SPECT/CT).

A total of 833 SLNs were removed from 403 patients. The researchers found 2.40 SLNs per patient in the SPECT/CT group and 1.87 SLNs per patient in the standard group; 51 of 358 excised SLNs (14.2 percent) in the SPECT/CT cohort and 54 of 475 SLNs (11.4 percent) in the standard cohort showed metastatic involvement. The authors were able to identify 41 patients (27.5 percent) with positive SLNs in the SPECT/CT cohort and 48 (18.9 percent) with positive SLNs in the standard cohort. The number of positive SLNs per patient was significantly higher in the SPECT/CT cohort than in the standard cohort (0.34 vs. 0.21).

“The local relapse rate in the SPECT/CT cohort was lower than in the standard cohort (6.8 percent vs. 23.8 percent,), which prolonged 4-year disease-free survival (93.9 percent vs. 79.2 percent),” the researchers write.

The authors note that with the SPECT/CT technique, they were able to use smaller incisions in the head and neck area as well as alternative entry points due to the exact anatomical localization of the SLN.

“In conclusion, the preoperative visualization of SLN with SPECT/CT is technically feasible and facilitates the detection of additional positive SLNs. The use of this technique offers the physician the preoperative possibility of determining the exact location and visualization of the SLN …”, the researchers write. “In patients with cutaneous melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone was associated with higher detection of metastatic involvement and a higher rate of disease-free survival.”

(JAMA. 2012;308[10]:1007-1014. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was not supported by any grant or sponsor. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact William J. Calhoun, M.D., call Raul Reyes at 409-747-0794 or email rareyes@utmb.edu. To contact editorial co-author George T. O’Connor, M.D., M.S., call Gina DiGravio at 617-638-8480 or email gina.digravio@bmc.org.

CHICAGO – Among adults with asthma controlled with low-dose inhaled corticosteroid therapy, the time to treatment failure was not significantly different among patients who received corticosteroid dose adjustment based on physician assessment, a biomarker, or symptom occurrence, according to a study in the September 12 issue of JAMA.

Asthma disease activity varies daily, seasonally, and episodically, presumably related to airway inflammation. “Accordingly, asthma management requires periodic dose adjustments of controller medications, particularly inhaled corticosteroids. Adjustments have been based on (1) physician assessment of symptoms, activity limitation, rescue albuterol use (a bronchodilator used for treating asthma), lung function, and exacerbations at usual office or clinic visits, (2) a biomarker of disease activity (e.g., exhaled nitric oxide), or (3) the occurrence of symptoms on a day-to-day basis,” according to background information in the article. “No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma.”

William J. Calhoun, M.D., of the University of Texas Medical Branch, Galveston, and colleagues hypothesized that adjustment of inhaled corticosteroids based on symptoms or measurement of exhaled nitric oxide would be superior to adjustment based on physician assessment. The researchers conducted a randomized, placebo-controlled trial that included 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]). The Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. For physician assessment-based adjustment and biomarker-based adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.

The researchers found that the time to treatment failure, the primary study outcome, did not differ significantly among the 3 treatment strategies. The 9-month Kaplan-Meier failure rates were 22 percent (24 events) for physician assessment-based adjustment (PABA), 20 percent (21 events) for biomarker-based adjustment (BBA), and 15 percent (16 events) for symptom-based adjustment (SBA).

Treatment failure rates were not different among groups when multiple episodes of treatment failure were included. There were not significant differences among the treatment groups for asthma exacerbation (including multiple episodes) rates; and the average proportion of treatment failures that progressed to exacerbations. The authors also found that measures of lung function and asthma symptoms were not significantly different among the groups.

“In summary, among adult participants with mild to moderate persistent asthma, neither the SBA nor the BBA strategy for inhaled corticosteroid therapy was superior to the standard PABA strategy for the outcome of treatment failure.”

(JAMA. 2012;308[10]:987-997. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, September 11 at this link.

Editorial: Inhaled Corticosteroid Dose Adjustment in Mild Persistent Asthma

In an accompanying editorial, George T. O’Connor, M.D., M.S., of the Boston University School of Medicine, (and Contributing Editor, JAMA), and Joan Reibman, M.D., of New York University, New York, comment on the findings of this study.

“This report adds to prior randomized trials that have compared the typical physician-prescribed dosing of inhaled corticosteroids (ICS) with intermittent dosing guided by symptoms for patients with relatively mild asthma. A prior Asthma Clinical Research Network (ACRN) study of adults with mild persistent asthma indicated that a strategy of initiating a course of inhaled or oral corticosteroid only when asthma symptoms became bothersome (according to a written action plan), led to a similar peak expiratory flow rate and asthma exacerbation rate as the everyday physician-prescribed dosing of controller medications (ICS or leukotriene antagonist), although some outcomes such as bronchial reactivity and symptom-free days were improved by regular twice daily use of ICS. Like the BASALT trial, the prior ACRN study was designed to show superiority of one strategy over another, rather than to test equivalence, and the lack of superiority of any strategy over the others must be interpreted accordingly.”

(JAMA. 2012;308[10]:1036-1037. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact corresponding author Moses S. Elisaf, M.D., Ph.D., F.A.S.A., F.R.S.H., email egepi@cc.uoi.gr.

CHICAGO – In a study that included nearly 70,000 patients, supplementation with omega-3 polyunsaturated fatty acids was not associated with a lower risk of all-cause death, cardiac death, sudden death, heart attack, or stroke, according to an analysis of previous studies published in the September 12 issue of JAMA.

“Treatment with marine-derived omega-3 polyunsaturated fatty acids (PUFAs) for the prevention of major cardiovascular adverse outcomes has been supported by a number of randomized clinical trials (RCTs) and refuted by others. Although their mechanism of action is not clear, their postulated effect on cardiovascular outcomes may be due to their ability to lower triglyceride levels, prevent serious arrhythmias, or even decrease platelet aggregation and lower blood pressure. Current guidelines issued by major societies recommend their use, either as supplements or through dietary counseling, for patients after myocardial infarction [MI; heart attack], whereas the U.S. Food and Drug Administration has approved their administration only as triglyceride-lowering agents in patients with overt hypertriglyceridemia, and some (but not all) European national regulatory agencies have approved the omega-3 administration for cardiovascular risk modification. The controversy stemming from the varying labeling indications causes confusion in everyday clinical practice about whether to use these agents for cardiovascular protection,” according to background information in the article.

Evangelos C. Rizos, M.D., Ph.D., of the University Hospital of Ioannina, Ioannina, Greece, and colleagues performed a large-scale synthesis of the available randomized evidence by conducting a systematic review and meta-analysis to determine the association between omega-3 PUFAs and major cardiovascular outcomes.

Of the 3,635 citations retrieved, 20 studies with 68,680 randomized patients were included, reporting 7,044 deaths, 3,993 cardiac deaths, 1,150 sudden deaths, 1,837 heart attacks, and 1,490 strokes. Analysis indicated no statistically significant association with all-cause mortality, cardiac death, sudden death, heart attack, and stroke when all supplement studies were considered.

“In conclusion, omega-3 PUFAs are not statistically significantly associated with major cardiovascular outcomes across various patient populations. Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration. Randomized evidence will continue to accumulate in the field, yet an individual patient data meta-analysis would be more appropriate to refine possible associations related to, among others, dose, adherence, baseline intake, and cardiovascular disease risk group,” the authors conclude.

(JAMA. 2012;308[10]:1024-1033. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Elisaf reported having given talks, attended conferences, and participated in trials sponsored by industry not associated with those that manufacture or market omega-3 supplements.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Prone Position During Breast Cancer Radiation Therapy Associated With Reduced Amount of Irradiation to Lung, Heart

Radiation therapy to the breast contributes to improved outcomes in breast cancer patients after breast preservation surgery. “However, whole breast radiotherapy is associated with damage to the heart and lung, increased cardiovascular mortality, and lung cancer development, with risks that remain 15 to 20 years after treatment. These consequences occur when breast cancer patients are treated supine [lying on their back]. Preliminary data on prone positioning [lying face downward] suggest that radiation exposure to the heart and lung can be reduced compared with supine positioning with similar efficacy,” writes Silvia C. Formenti, M.D., of the New York University School of Medicine, New York, and colleagues.

As reported in a Research Letter, the authors conducted a study to test the hypothesis that prone positioning is superior to standard supine positioning, comparing the volume of heart and lung within the radiation field. The prospective study included breast cancer patients who underwent 2 computed tomography (CT) simulation scans, first supine and next prone. Two hundred patients per stratum (left and right breast cancer) were enrolled. The researchers found that prone positioning was associated with a reduction in the amount of irradiated lung in all patients and in the amount of heart volume irradiated in 85 percent of patients with left breast cancer. “The study is limited to a single institution. A multi-institutional prospective trial with outcome measures is warranted to confirm these findings. If prone positioning better protects normal tissue adjacent to the breast, the risks of long-term deleterious effects of radiotherapy may be reduced.”

(JAMA. 2012;308[9]:861-863. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

The Safety Risks of Innovation – The FDA’s Expedited Drug Development Pathway

Thomas J. Moore, A.B., of the Institute for Safe Medication Practices, Alexandria, Va., and Curt D. Furberg, M.D., Ph.D., of the Wake Forest School of Medicine, Winston-Salem, N.C., examine the FDAs program for speeding approval of new drugs, known officially as the “Expedited Drug Development Pathway.” The authors discuss the complex safety issues raised by the expedited approval process, and cite three examples involving drugs for treatment of cancer, multiple sclerosis, and stroke prevention, with these new drugs including some agents with limited clinical trial data and substantial risks.

“It takes years of development, costly clinical trials, and extensive analyses to establish the clinical conditions under which new drugs will do more good than harm. Risks persist, even with standard approvals. Meanwhile, the U.S. Senate, in approving a regular 5-year update to the Food, Drug, and Cosmetic Act, proposed a further expansion of expedited review, with a new category for ‘breakthrough drugs.’ For physicians, the FDA’s emphasis on rapid drug approval underlines the importance of the 6 ‘principles of conservative prescribing’ that include the warning, ‘Exercise caution and skepticism regarding new drugs.’”

(JAMA. 2012;308[9]:869-870. Available pre-embargo to the media at http://media.jamanetwork.com)

Clinical Trial Data as a Public Good

Marc A. Rodwin, J.D., Ph.D., of Harvard University, Cambridge, Mass., and John D. Abramson, M.D., M.S., of Harvard Medical School, Boston, discuss the need to improve public access to clinical trial data, and suggest mandatory disclosure of the standardized Clinical Study Report (CSR) for all clinical trials involving FDA-approved drugs.

The CSR summarizes the trial, clinical end points, methods, key data, and data analysis and includes the most pertinent information about a clinical trial in an easily analyzed format. “Drug manufacturers already produce these reports to meet international and national regulatory requirements. Making CSRs publicly available would not be expensive, yet disclosure would promote research integrity, medical knowledge, and public health. Furthermore, CSRs are more likely to be reliable than other summaries. Drug manufacturers submit CSRs to public authorities when they seek marketing approval and cannot alter or delete data without potentially jeopardizing their relationships with regulatory agencies and risking criminal prosecution,” the authors write.

They add that “to expand public access to clinical trial data, Congress could require the FDA to disclose all CSRs that drug manufacturers submit when seeking marketing approval and also could require drug firms to disclose CSRs for all clinical trials they conduct for drugs that they market in the United States. Those actions would go a long way toward making the knowledge derived from clinical trials truly a public good.”

(JAMA. 2012;308[9]:871-872. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Media Advisory: To contact corresponding author Maria E. Suarez-Almazor, M.D., Ph.D., call Julie Penne at 713-792-0662 or email jpenne@mdanderson.org.

CHICAGO – Although there are concerns regarding the potential development of malignancies in patients with rheumatoid arthritis who are receiving treatment with biologic response modifiers (BRMs), pooled results from more than 60 randomized controlled trials did not find a statistically significant increased risk of any type of cancer with use of BRMs for at least 6 months compared with traditional disease-modifying antirheumatic drugs or with placebo, according to the results of a meta-analysis published in the September 5 issue of JAMA.

“Rheumatoid arthritis (RA) is a systemic inflammatory polyarthritis that can lead to significant morbidity, joint deformity, and impaired quality of life and affects approximately 1 percent of the general population. Treatment with traditional disease-modifying antirheumatic drugs (DMARDs) reduces disease activity, retards joint destruction, and improves patients’ quality of life. However, in many patients with active disease, traditional DMARDs fail or are not tolerated. Biologic response modifiers provide clinically important improvement in patients not responding to traditional DMARDs by targeting specific immune pathways, reducing inflammation, and leading to better control of symptoms and structural damage. In 2010, published data from European and U.S. registries reported that 25 percent to 56 percent of patients with RA used BRMs,” according to background information in the article.

The authors add that because these biologic agents interfere with the immune system, concerns exist regarding their safety, specifically with respect to infections and malignancies. “Since 2005, conflicting data have existed associating tumor necrosis factor (TNF) inhibitors with an increased risk of developing certain types of malignancies.”

Maria A. Lopez-Olivo, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center, Houston, and colleagues conducted a study to evaluate the risk of developing any type of malignancy in patients with RA receiving treatment with BRMs. The authors searched the medical literature to identify randomized controlled trials that included the BRMs abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Studies were selected that compared the safety of any BRMs used in RA patients with placebo and/or any traditional DMARDs with a minimum of 24 weeks of follow-up.

The researchers identified 63 RCTs with 29,423 patients for inclusion in the analysis. No statistically significant increased risk of developing malignancy was observed. Of the 29,423 patients, 211 developed a malignancy during the trial (0.72 percent): 23 of 3,615 patients in the BRM monotherapy group (0.64 percent), 123 of 15,989 patients in the BRM combination therapy group (0.77 percent), and 65 of 9,819 patients in the control group (0.66 percent).

“Of the 211 malignancies, 118 were solid tumors (i.e., adrenal, bladder, breast, cholangiocarcinoma, fibrosarcoma, gastrointestinal, hepatic, leiomyosarcoma, liposarcoma, lung, ovarian, pancreatic, prostate, renal, testicular, thyroid, tongue, uterine), 48 were skin cancers (i.e., basal cell, squamous cell, and 4 melanomas), 14 were lymphomas, 26 were not specified, and 5 were hematologic nonlymphoma (i.e., multiple myeloma, leukemia),” the authors write.

No statistically significant risk was observed for specific cancer sites. Anakinra plus methotrexate showed lower odds compared with methotrexate alone.

“Overall, our findings do not support an increased risk of malignancy for patients with RA receiving BRMs in RCTs of at least 24 weeks’ duration. Additional systematic reviews of observational studies are needed to establish risk in the longer term. Although the findings suggest that BRMs may be generally safe with respect to risk of malignancy in the short term, the risk of recurrence in patients with RA with history of cancer or cancer risk factors remains unknown,” the authors conclude.

(JAMA. 2012;308[9]:898-908. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was not funded or supported by any organization. Dr. Suarez-Almazor has a K24 career award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Media Advisory: To contact Charlotte Andersson, M.D., Ph.D., email ca@heart.dk. To contact editorial author Deepak L. Bhatt, M.D., M.P.H., call Lori Schroth at 617-534-1604 or email ljschroth@partners.org.

CHICAGO – In a study that included nearly 60,000 patients with a first-time heart attack, patients with diabetes who received conventional platelet-inhibition with clopidogrel had a lower reduction in the risk of all-cause death and cardiovascular death compared with heart attack patients without diabetes who received clopidogrel, according to a study in the September 5 issue of JAMA.

“Patients with diabetes have an increased risk of ischemic adverse events and death compared with patients without diabetes,” according to background information in the article. “Pharmacodynamic studies have shown that persistently high platelet reactivity is common in patients with diabetes in spite of clopidogrel treatment. Clinical trials have not convincingly demonstrated that clopidogrel benefits patients with diabetes as much patients without diabetes.”

Charlotte Andersson, M.D., Ph.D., of Gentofte Hospital, Hellerup, Denmark, and colleagues analyzed the outcomes associated with clopidogrel treatment after heart attack in patients with and without diabetes.  The study included data from the Danish nationwide administrative registries between 2002-2009 of patients who were hospitalized with incident heart attack and who had survived and not undergone coronary artery bypass surgery 30 days after discharge and who were followed up for as long as 1 year. Analysis was conducted to investigate the association between clopidogrel treatment in patients with and without diabetes and the outcomes of all-cause mortality, cardiovascular mortality, and a composite end point of recurrent heart attack and all-cause mortality.

Of the 58,851 patients—7,247 of whom (12 percent) had diabetes—who were included in the analyses, 35,380 (60 percent) received clopidogrel at the beginning of the study. Patients were followed up for a median (midpoint) of 365 days. In total, 1,790 patients (25 percent) with and 7,931 patients (15 percent) without diabetes met the composite end point. Of these, 1,225 (17 percent) with and 5,377 (10 percent) without diabetes died. Of the patients who died, 978 patients (80 percent) with and 4,100 patients (76 percent) without diabetes died of cardiovascular-related events.

Of patients with diabetes, those who took clopidogrel had lower crude incidence rates of all-cause mortality than those who were not taking clopidogrel. Of patients who did not have diabetes, those who took clopidogrel had lower crude incidence rates of all-cause mortality than those who did not take clopidogrel. Adjusted for other variables, patients with diabetes were found to have a smaller relative risk reduction for mortality than patients without diabetes. “When adjusted, this finding applied for the all-cause mortality end point and the cardiovascular mortality end point, but not for the composite end point,” the authors write.

“In the present analysis, clopidogrel treatment was associated with a relative risk reduction of 25 percent for all-cause mortality, 23 percent for cardiovascular mortality, and 9 percent for the combination of recurrent myocardial infarction [MI; heart attack] and all-cause mortality in patients without diabetes, and a relative risk reduction of 11  percent for all-cause mortality but no significant reduction in cardiovascular mortality or the combined end point in patients with diabetes.”

“In summary, data from previous clinical trials and data from the present analyses strongly suggest that patients with diabetes have a significantly diminished relative effectiveness of conventional platelet-inhibition with clopidogrel after MI compared with patients without diabetes. It should however be emphasized that considering the relatively higher absolute risks found for patients with diabetes, use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes, which data from the subgroup analyses supported. Available data nevertheless raise a possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes,” the researchers conclude.

(JAMA. 2012;308[9]:882-889. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The study was funded by an internal research foundation grant at the Department of Cardiology, Gentofte Hospital. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Antiplatelet Therapy Following Myocardial Infarction in Patients With Diabetes

Deepak L. Bhatt, M.D., M.P.H., of the VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, writes in an accompanying editorial that the “study by Andersson et al highlights the elevated risk of recurrent myocardial infarction and cardiovascular mortality among patients with diabetes following MI.”

“More needs to be done to reduce these risks among such patients. At least a portion of this excess risk appears due to platelet activity and function and to the effects of antiplatelet medications in patients with diabetes. Therefore, in appropriately selected patients, intensification of the antiplatelet regimen may be one method by which their outcomes might be markedly improved.”

(JAMA. 2012;308[9]:921-922. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Media Advisory: To contact corresponding author Andrew E. Arai, M.D., call Nick Zagorski at 301-496-4236 or email nicholas.zagorski@nih.gov.

CHICAGO – Using cardiac magnetic resonance imaging among older adults in Iceland, researchers estimated the prevalence of unrecognized heart attacks, which was associated with an increased risk of death, according to a study in the September 5 issue of JAMA.

“The prevalence and prognosis of unrecognized myocardial infarction [MI; heart attack] in older people with and without diabetes may be higher than previously suspected in population studies. Advances in MI detection, such as cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE), are more sensitive than prior methods. Ascertaining the prevalence of unrecognized MI (UMI) in these groups is relevant because age and diabetes increase the risks of coronary heart disease. Pathologic studies indicate that subclinical coronary plaque rupture occurs frequently, particularly in diabetic individuals, which may culminate in a high prevalence of UMI,” according to background information in the article.

Erik B. Schelbert, M.D., M.S., of the National Institutes of Health, Bethesda, Md., and colleagues conducted a study to compare the prevalence and prognosis of recognized and unrecognized MI diagnosed with CMR vs. electrocardiography (ECG) in older diabetic and nondiabetic participants. ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling group of older individuals in Iceland, data for 936 participants ages 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. The median (midpoint) age was 76 years, and 52 percent of the participants were women.

A total of 91 of 936 participants (9.7 percent) had recognized myocardial infarction (RMI), and the prevalence of UMI by CMR was 17 percent (157/936). Those with diabetes had a higher prevalence of UMI by CMR than those without diabetes (n=72; 21 percent, vs. n=85; 14 percent). Cardiac magnetic resonance detected 157 UMI, which was more than the 46 UMI detected by ECG (prevalence by CMR, 17 percent; vs. ECG, 5 percent, respectively). “In the randomly sampled cohort (n=670), 61 participants (9 percent) had RMI and 97 (14 percent) had UMI by CMR whereas only 35 (5 percent) had UMI by ECG, significantly less than UMI by CMR,” the authors write. Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease.

Over a median follow-up of 6.4 years, 30 of 91 participants with RMI died (33 percent), and 44 of 157 with UMI by CMR died (28 percent), which were both significantly higher rates than the 17 percent with no MI who died (119/688). After adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (absolute risk increase, 8 percent), but UMI by ECG was not associated with mortality (absolute risk increase, -2 percent).

The researchers add that they observed more use of aspirin, β-blocker, and statin medications in those with UMI by CMR compared with those without MI. “Yet the use of cardiac medications was significantly less in those with UMI compared with those with RMI. Roughly half of those with UMI were taking aspirin, whereas less than half were taking statins or β-blockers.”

The authors suggest that several factors may contribute to the high prevalence of UMI. “First, subclinical coronary plaque rupture occurs frequently, particularly in diabetic individuals. Cardiac magnetic resonance may detect the myocardial sequelae of coronary plaque rupture or coronary plaque erosion that either spontaneously reperfused or were nonocclusive. Second, symptom variation in acute MI may lead patients or their clinicians to attribute MI symptoms to noncardiac causes. Third, given their propensity to be clinically detected, RMI may be more severe than UMI and impart greater lethality.”

“This investigation also suggests limitations in current prevention strategies. Herein we report a burden of MI in community-dwelling older individuals that is higher than previously appreciated. The burden of UMI was higher than the total burden of recognized MI, and prescription of cardioprotective medications was less than for participants with RMI. The high prevalence of MI specifically in individuals with diabetes confirms their increased vulnerability. Less than one-third of those with UMI by CMR had prior revascularization to establish coronary disease and trigger secondary prevention strategies. Detection of UMI by CMR may provide an opportunity to optimize treatment for these vulnerable individuals, but further study is needed to assess this.”

(JAMA. 2012;308[9]:890-897. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Media Advisory: To contact corresponding author Gary F. Mitchell, M.D., call 781-255-6930 or email garyfmitchell@gmail.com. To contact editorial author Debabrata Mukherjee, M.D., M.S., call Laura Gallegos at 915-309-5647 or email laura.gallegos@ttuhsc.edu.

CHICAGO – An analysis of the relationship between several vascular function measures and blood pressure levels finds that certain measures including higher aortic stiffness were associated with a higher risk of new hypertension; however, initial blood pressure was not independently associated with risk of progressive aortic stiffening, suggesting that vascular stiffness may be a precursor rather than the result of hypertension, according to a study in the September 5 issue of JAMA.

“Vascular stiffness increases with advancing age and is a major risk factor for age-related morbidity and mortality. A compliant aorta provides an important buffer for each ventricular contraction that maintains pulse pressure at low levels. Stiffening of the aortic wall and improper matching between aortic diameter and flow are associated with unfavorable alterations in pulsatile hemodynamics, including an increase in forward arterial pressure wave amplitude, which increases pulse pressure,” according to background information in the article. “The association between vascular stiffening and blood pressure is particularly interesting because the functional relationship is likely bidirectional. Elevated blood pressure may cause vascular damage and accelerated conduit artery stiffening. Conversely, aortic stiffening increases pressure pulsatility and therefore affects systolic blood pressure. However, temporal relationships between vascular stiffness and blood pressure remain incompletely elucidated. In particular, whether vascular stiffness antedates hypertension or vice versa is unclear.”

Bernhard M. Kaess, M.D., of the National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Mass., and colleagues the examined temporal relationship between vascular stiffening and blood pressure by evaluating vascular stiffness, central hemodynamics, peripheral blood pressure, and incident hypertension. The investigation was based on the 2 latest examination cycles (cycle 7: 1998-2001; cycle 8: 2005-2008 [last visit: January 25, 2008]) of the Framingham Offspring study (recruited: 1971-1975). Temporal relationships among blood pressure and 3 measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoral pulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examined over a 7-year period in 1,759 participants (average age, 60 years). The primary outcome measures were blood pressure and incident hypertension during examination cycle 8. The secondary outcomes were CFPVW, FWA, and augmentation index during examination cycle 8.

The researchers found that aortic stiffness, central FWA, and wave reflection were jointly associated with future systolic blood pressure, pulse pressure, and incident hypertension. Initial blood pressure traits were associated with future FWA and augmentation index but not with aortic stiffness assessed by CFPWV.

Brachial artery measures of microvascular resistance and endothelial function were jointly associated with incident hypertension after considering blood pressure and tonometry variables.

“Our data suggest that aortic stiffness, central pressure pulsatility, peripheral wave reflection, large artery endothelial function, and microvascular function jointly antedate and potentially contribute to the development of clinical hypertension. Arterial stiffness and function may therefore be important potential targets for interventions aimed at preventing incident hypertension,” the authors write.

(JAMA. 2012;308[9]:875-881. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported through contracts with the National Institutes of Health, National Heart, Lung, and Blood Institute, and a grant from the Donald W. Reynolds Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Atherogenic Vascular Stiffness and Hypertension – Cause or Effect?

In an accompanying editorial, Debabrata Mukherjee, M.D., M.S., of the Texas Tech University Health Sciences Center, El Paso, writes that the “implications of the study by Kaess et al for prevention may be substantial.”

“By concentrating on the underlying drivers of chronic diseases like hypertension and atherosclerosis, clinicians may be able to move from today’s sick care system to a true health care system that encourages health and well-being. If prospective studies validate both prevention of hypertension and improved cardiovascular outcomes using lifestyle modifications as well as a combination therapy approach in individuals with vascular stiffness, endothelial dysfunction, or both, before hypertension develops, such a strategy could become a cornerstone of a national preventive strategy.”

(JAMA. 2012;308[9]:919-920. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of interest and reported receiving royalties from Lippincott Williams & Wilkins for editing 1001 Questions: An Interventional Cardiology Board Review and from Informa Healthcare Books for editing Cardiovascular Catheterization and Intervention.

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